RU2448974C2 - iRNK-INHIBITION OF INFLUENZA VIRUS REPLICATION - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: inventions relate to field of biotechnology. iRNK-agents contain sense strand, where said sense strand contains in internal area 15-30 successive nucleotides, which differ from nucleotides of SEQ ID NO:427 sequence not more than by one nucleotide, and antisense strand, where said antisense strand contains in internal area 15-30 successive nucleotides, which differ from nucleotide of SEQ ID NO:428 sequence by not more than one nucleotide.

EFFECT: iRNA agents can contain modifications, which increase their stability in biological sample, cholesterol molecule, non-natural nucleotide base, iRNA-agents are applied for inhibition of expression of PB2 gene of influenza A virus.

73 cl, 9 dwg, 6 tbl, 3 ex

Description

Cross reference to related applications

This application claims the priority of a US patent application reg. No. 60/732243, filed November 1, 2005; US Patent Application Reg. No. 60/748317, filed December 7, 2005; and US Patent Reg. No. 60/799000, filed May 9, 2006. The contents of each of these provisional applications in their entirety is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the treatment of influenza and to compositions and methods used to modulate the replication of the virus, and more particularly to downregulate the influenza virus gene (s) using oligonucleotides that act by RNA interference and which are introduced locally into the lungs and nasal passages by inhalation / intranasally or systemically, for example by intravenous injection.

State of the art

The term RNA or “RNAi” was first coined by Fire and co-workers to describe observations that revealed that when double-stranded RNA (dsRNA) was injected into worms, it could block gene expression (Fire et al., Nature 391: 806 -811, 1998). Short-chain dsRNA regulates gene-specific post-transcriptional silencing in many organisms, including vertebrates, and is used as a new tool for studying gene function. Recently, this technology has been described many times in the literature D, see, e.g., publication Novina, CD & Sharp, P., Nature 2004, 430:. 161, and Sandy, P., et al, Biotechniques 2005, 39:. 215, which are incorporated herein by reference.

Influenza is one of the most widespread infectious diseases worldwide. This may seem unbelievable, but, according to experts, in 1918, from 20 to 40 million people died from a flu pandemic caused by the strain A virus. In the United States, between 20 and 40 thousand people die each year from influenza caused by the strain A virus or its complications. During epidemics in just one winter, the number of hospital admissions for influenza can reach 300,000.

The epidemiological spread of the influenza virus is favored by some properties of the virus. Firstly, it is easily transmitted from person to person by airborne droplets (airborne infection). Secondly, small changes (antigenic drift) often occur in the antigens of the influenza virus, as a result of which this virus easily “eludes” the immune “surveillance” induced by the preliminary exposure to another variant of this virus. Third, by reassorting or mixing the genetic material of different strains (antigenic drift), new strains of the influenza virus can be easily produced. In the case of influenza A virus, such mixing can occur between subtypes or strains that infect organisms of various species. It is believed that the 1918 pandemic was caused by the emergence of a hybrid strain of the virus produced as a result of the reassortment of the swine and human influenza A viruses. Currently, there is a great danger of the possible spread of new influenza strains that are infectious to humans, in particular, bird flu variants, and more specifically strain H5N1, which are formed as a result of mixing human and avian viruses with their simultaneous effects on humans. Experts no longer question the fact that the close contact between poultry and poultry farmers in many Asian countries will lead to the emergence of such a mixed strain, and they are convinced that this is only a matter of time. With the rapid development of such a pandemic throughout the world, its consequences can be much more serious than in 1918.

Despite the tremendous efforts currently being made, effective methods for treating influenza virus infections have not yet been developed, and the effects of existing vaccines are partly limited by their tendency to antigenic variation and antigenic drift, as indicated above. For these reasons, global studies of influenza A virus have been ongoing for many years, and the US National Institute of Health has named these studies one of the top priorities in the fight against viral pathogens. Although modern vaccines based on inactivated viruses can prevent the disease in approximately 70-80% of healthy individuals under the age of 65, this percentage is much lower in older individuals or in individuals with impaired immunity. In addition, the high cost of these vaccines and the possible side effects associated with the administration of these vaccines reduce the effectiveness of such vaccines to below optimal levels. Although current antiviral drugs approved for use in the United States are effective in the treatment and / or prevention of influenza, they are of limited use due to side effects, the inconvenience of their use by the patient and the possible emergence of resistant strains.

In the application for US patent 20040242518 and in the corresponding application WO 04/028471, filed September 29, 2003, a small number of RNAi agents for the treatment of influenza. However, their effectiveness for humans is not described.

Therefore, the need to develop effective therapy aimed at treating and preventing infections caused by the influenza virus in humans and animals, and in particular highly effective therapy aimed at destroying subtypes of the influenza virus of a wide range, remains relevant. One of the necessary conditions for the high efficiency of therapy is the slow decomposition of the active ingredient in physiological conditions.

Description of the invention

The present invention is based on the discovery in vitro and in vivo of the fact that influenza virus infection can be inhibited by intranasal administration of mRNA agents, as well as by parenteral administration of such agents and identification of effective mRNA agents that originate from MP genes, Influenza virus NP, PB1, PB2, or PA, and which can lower the flu virus RNA levels of certain subtypes. Based on this, the present invention has been developed that relates to specific compositions and methods used to reduce influenza virus mRNA levels, influenza virus protein levels and influenza virus titers in an individual, for example, a mammal, such as a human.

The present invention, in particular, relates to mRNA agents, including either consisting or mainly consisting of at least 15 or more adjacent nucleotides of one of the influenza virus genes, and in particular the MP, NP, PB1, PB2 genes and PA of influenza virus, and more specifically to agents containing 15 or more adjacent nucleotides of one of the sequences shown in tables 1A-1H. The mRNA agent preferably contains less than 30 nucleotides per chain, for example 21-23 nucleotides, such as the nucleotides described in tables 1A-1H. The double-stranded mRNA agent can either have blunt ends, or it can, preferably, have protruding ends, consisting of 1-4 nucleotides located on the side of one or both 3'-ends of this agent.

In addition, the mRNA agent can contain either only natural ribonucleotide subunits, or it can be synthesized so that it contains one or more modifications of sugar or bases in one or more ribonucleotide subunits included in this agent. The mRNA agent can be further modified so that it is attached to a ligand selected in order to increase the stability, distribution or absorption of a substance, for example cholesterol, in cells. mRNA agents can also be obtained in a separate form or they can be part of the pharmaceutical composition used in the methods described here, and in particular in a pharmaceutical composition intended for delivery to the lungs or nasal passages or for parenteral administration. Such pharmaceutical compositions may contain one or more mRNA agents, and in some embodiments of the invention they may contain two or more mRNA agents, each of which is directed to different segments of the influenza virus gene or to different genes of the influenza virus.

In one of its aspects, the present invention relates to a double-stranded oligonucleotide containing at least one non-natural nucleotide base. In some embodiments of the invention, such an unnatural nucleotide base is difluorotolyl, nitroindolyl, nitropyrrolyl or nitroimidazolyl. In a preferred embodiment of the invention, such an unnatural nucleotide base is difluorotolyl. In some embodiments of the invention, only one of the two oligonucleotide chains including a double-stranded oligonucleotide contains a non-natural nucleotide base. In some embodiments of the invention, both oligonucleotide chains comprising a double-stranded oligonucleotide independently contain a non-natural nucleotide base.

The present invention also relates to methods for reducing the level of influenza virus RNA in a cell. Such methods include the step of administering one of the mRNA agents of the invention to an individual, described in detail below. The methods of the invention utilize cellular mechanisms involved in RNA interference resulting in the selective destruction of viral RNA in the cell, and such methods include the step of contacting the cell with one of the antiviral mRNA agents of the invention. Such methods can be carried out directly on the cells, or they can be carried out by administering to the individual mammal one of such means as mRNA agents / pharmaceutical compositions according to the invention. A decrease in the level of viral RNA in the cell leads to a decrease in the amount of viral protein produced, and in the body of the individual to a decrease in the titer of the replicating virus (as shown in the examples).

The methods and compositions according to the invention, for example methods that use an mRNA agent, and compositions containing an mRNA agent, can be used in any of the dosage forms and / or preparations described herein, and such forms and preparations can also be administered by any of the methods described here. A particularly important aspect of the present invention is the intranasal administration of an mRNA agent and its ability to inhibit virus replication in respiratory tract tissues.

A detailed description of one or more embodiments of the present invention is given below in the description of the graphic material and in the description of the invention. Other features, objects and advantages of the invention will be more apparent from the description of the invention, from the graphic material and from the claims. All works, patents, and patent applications cited herein are hereby incorporated by reference in their entirety and for all purposes.

A brief description of the graphic material

FIG. 1A-1I: Dose-response curves illustrating inhibition of target gene expression using selected RNAi agents. The corresponding target gene was recombinantly cloned in the plasmid into Cos-7 cells, resulting in the expression of mRNA encoding the target gene and Renilla luciferase, and then these cells were treated with an RNAi agent and the amount of Renilla luciferase was determined. Cells were treated with an RNAi agent at concentrations of 100 nM, 25 nM, 6.3 nM, 1.6 nM, 400 pM, 100 pM, 24 pM, 6 pM, 1.5 pM and 380 fM and IC ₅₀ values were determined by constructing a parametric curve using XLfit.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “influenza virus” means any strain of influenza virus that is capable of causing disease in animals or humans, or that is of interest as a candidate for experimental analysis. Influenza viruses are described in Fields, B., et al., Fields' Virology, 4 ^th ed. 2001, Lippincott Williams and Wilkins; Philadelphia, ISBN: 0781718325. In particular, this term includes any strain of influenza A virus that is capable of causing disease in an animal or human, or that is of interest as a candidate for experimental analysis. A large number of influenza A virus isolates were partially or completely sequenced. Table 6 provides only an incomplete list of full-length sequences of influenza A genome segments that were deposited in a public database (influenza virus sequence database (ISD), see Macken, C, Lu, H., Goodman, J., & Boykin, L., "The value of a database in surveillance and vaccine selection." In Options for the Control of influenza IV. ADME Osterhaus, N. Cox & AW Hampson (Eds. ) 2001, Elsevier Science, Amsterdam, pp 103-106). This database also contains full-length sequences of segments of the genome of the influenza virus B and C. This database is available on the Internet and includes a convenient search mechanism that allows the user to search by genome segments, by species infected with the virus, and by year of strain isolation. Influenza virus sequences are also available in the Genbank database. Therefore, the sequences of the influenza virus genes are easily accessible to the average person skilled in the art, or they can be easily determined by one skilled in the art.

For a better understanding of the terms “nucleotide” or “ribonucleotide” used herein, it should be noted that sometimes these terms apply to one or more monomeric subunits of an RNA agent. In addition, it should be noted that the term “ribonucleotide” or “nucleotide” as used herein, if it refers to a modified RNA or nucleotide substitute, also means a modified nucleotide or a substituting part thereof, described in detail below, in one or more positions .

As used herein, the term “RNA agent” means unmodified RNA, modified RNA, or a nucleoside substitution, each of which is described herein and is well known to those skilled in the art of RNA synthesis. Although many modified RNAs and nucleoside substitutions are described herein, however, preferred examples are molecules that are more resistant to nuclease digestion than unmodified RNAs. Preferred examples are molecules having a 2'-position modification of sugar , Modification of a single stranded protruding end, and in particular the protruding single-stranded 3'-end, or, in the case of a single-stranded molecule, the 5 'modification which includes one or more phosphate groups or one or more analogs of a phosphate group.

As used herein, the term “mRNA agent” (this abbreviation means “interfering RNA agent”) means an RNA agent that can inhibit the expression of a target gene, for example, influenza virus. Not limited to any theory, it should be noted that the mRNA agent can act by one or several mechanisms, including post-transcriptional cleavage of the mRNA target, sometimes called RNAi specialists, or by pre-transcriptional or pre-translational mechanisms. The mRNA agent may be a double stranded mRNA agent.

As used herein, the “ds-mRNA agent" (the abbreviation means "double-stranded mRNA agent") is an mRNA agent having more than one, and preferably two strands, in which interchain hybridization can lead to the formation of a region with a duplex structure. As used herein, the term “chain” means a sequence of contiguous nucleotides (including non-natural or modified nucleotides). Such two chains or several chains can be separate molecules, or each of them can be part of separate molecules, or they can be covalently linked together, for example, by means of a linker, such as a polyethylene glycol linker, to form one molecule. At least one strand may include a region that is sufficiently complementary to the target RNA. Such a chain is called an “antisense chain”. The second strand of the dsRNA agent containing a region complementary to the antisense strand is called the “sense strand". However, the ds-mRNA agent can also be formed from a single RNA molecule, which is at least partially autocomplete, forming, for example, a hairpin structure or a structure that resembles a “pan handle” and includes a duplex region. The last of the structures mentioned above is called short hairpin RNA or cshRNA. In this case, the term “chain” means one of the regions of RNA molecules that is complementary to another region of the same RNA molecule.

In mammalian cells, long double-stranded mRNA agents can induce an interferon response, which is often undesirable, however, short double-stranded mRNA agents do not induce an interferon response, at least at a level that could adversely affect cells and / or the host organism (Manche et al., Mol. Cell. Biol. 12: 5238, 1992; Lee et al., Virology 199: 491, 1994; Castelli et al., J. Exp. Med. 186: 967, 1997; Zheng et al ., RNA 10: 1934, 2004; Heidel et al., "Lack of interferon response in animals to naked siRNAs" Nature Biotechn. Advance online publication doi: 10.1038 / nbtl038, Nov. 21, 2004). mRNA agents according to the invention include molecules that are sufficiently short, that is, they are not able to induce an undesirable non-specific interferon response in normal mammalian cells. So, for example, the introduction to the individual of a composition comprising an mRNA agent (for example, prepared as described in this application) can be carried out in order to reduce the level of expression of influenza virus genes in cells expressing the influenza virus in an individual, thereby avoiding the generation of an interferon response . Molecules that are sufficiently short and not capable of inducing an undesired interferon response are referred to herein as siRNA agents or siRNAs. As used herein, the term “siRNA agent” or “siRNA” means an mRNA agent, for example a ds-mRNA agent, that is short enough and not able to induce an undesired interferon response in mammalian cells, and in particular in human cells, for example, it has a duplex region containing less than 60, and preferably less than 50, 40, or 30 nucleotide pairs.

The isolated mRNA agents described herein, including ds mRNA agents and siRNA agents, can mediate a decrease in the expression level of an influenza virus nucleic acid, for example, by destroying RNA. For convenience, such RNA will also be referred to as silent RNA. Such a nucleic acid is also referred to herein as a target gene. Preferably, silent RNA is a gene product of an influenza virus gene that is part of a human strain of an influenza virus.

The term “RNAi mediated” as used herein means the ability of a given agent to sequentially inactivate a target gene. The term “target gene silencing” means a process in which a cell containing and / or expressing a specific product of the target gene, when it comes into contact with this agent, will contain and / or express at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% or less of the specified gene product compared to a similar cell that has not been in contact with this agent. seemed target gene product can be, for example, messenger RNA (mRNA), a protein or a regulatory element.

As used herein, the term “complementary” indicates a sufficient degree of complementarity, that is, stable and specific binding of a compound of the invention to a target RNA molecule, for example, influenza mRNA. For specific binding, a sufficient degree of complementarity is required, which avoids nonspecific binding of the oligomeric compound to non-target sequences under conditions in which specific binding is desirable, namely under physiological conditions, during in vivo assays or therapeutic treatment, or during performing in vitro assays under the conditions under which such assays are performed. Non-target sequences typically differ from target sequences by at least 2, 3 or 4 nucleotides.

The mRNA agent used here is “sufficiently complementary” to a target RNA, for example, an mRNA target (for example, an influenza virus mRNA target), if such an mRNA agent reduces the level of protein production encoded by the target RNA in the cell. Such an mRNA agent can also be “completely complementary” to an RNA target, such as a target RNA, and such an mRNA agent hybridizes, preferably to form a hybrid consisting solely of Watson-Crick base pairs in the region of absolute complementarity. A “sufficiently complementary” mRNA agent may include an internal region (for example, at least 10 nucleotides) that is completely complementary to the influenza virus RNA target. In addition, in some embodiments of the invention, the mRNA agent, in particular, differs in only one nucleotide. In this case, the mRNA agent mediates RNAi only if absolute complementarity occurs in a region (for example, of 7 nucleotides) differing in one nucleotide. Preferred mRNA agents are based on the sense and antisense sequences shown in tables 1A-1H, or they consist of or include these sequences.

As used herein, the term “substantially identical” when used in comparing a first nucleotide sequence with a second nucleotide sequence means that the first nucleotide sequence is identical to the second nucleotide sequence, with the exception of one, two or three nucleotide substitutions (for example, adenosine is replaced by uracil). As used herein, the term “essentially retains the ability to inhibit the expression of influenza virus in cultured cells expressing the human influenza virus” if it refers to an mRNA agent that is not identical to one of the mRNA agents shown in tables 1A-1H, but comes from one of these mRNA agents shown in tables 1A-1H, due to deletion, addition or replacement of nucleotides, means that such a derivative mRNA agent has an inhibitory activity of at least 20% of inhibitory a the activity of the mRNA agent shown in tables 1A-1H from which it is derived. For example, an mRNA agent derived from the mRNA agent shown in Tables 1A-1H and by 70% reduces the amount of influenza virus mRNA present in cultured human cells infected with the influenza virus can itself reduce the amount of influenza virus mRNA present in cultured human cells infected with influenza virus by at least 50%, which means that it essentially retains the ability to inhibit the replication of influenza virus in cultured human cells infected with the virus om flu. The mRNA agent according to the invention may, but not necessarily, reduce the amount of influenza virus mRNA present in cultured human cells infected with influenza virus by at least 50%.

As used herein, the term “individual” means a mammal undergoing treatment for a disorder mediated by influenza virus infection. Such an individual may be any mammal, such as a cow, horse, mouse, rat, dog, pig, goat or primate. In a preferred embodiment of the invention, said individual is a human.

Flu virus properties

Influenza viruses are viruses that have an RNA envelope and negative chain and belong to the Orthomyxovirus family. They are divided into subtypes A, B and C, of which the influenza A virus is the most pathogenic and probably represents one type that can undergo reassortment (shuffling) with animal strains. Influenza A, B, and C viruses may differ from one another in their nucleoproteins and matrix proteins. As discussed below, influenza A virus subtypes are determined by the difference in their hemaglutinin (HA) and neuraminidase (NA) genes and are usually identified by antibodies that bind to the corresponding proteins.

The genome of the influenza A virus consists of ten genes located in eight RNA segments. These genes encode 10 proteins: membrane glycoproteins: hemaglutinin (HA) and neuraminidase (NA); matrix protein (hereinafter referred to as M1 or MP); nucleoprotein (NP); three polymerases (PB1, PB2 and PA), which are components of an RNA-dependent RNA transcriptase, also referred to herein as a polymerase or polymerase complex; ion channel protein (M2) and non-structural proteins (NS1 and NS2). A more detailed description of influenza A virus and its molecular pathogenesis can be found in Julkunen, I., et al., Cytokine and Growth Factor Reviews, 12: 171-180, 2001. See also Fields, B., et al., Fields 'Virology, 4.sup.th. ed., Philadelphia: Lippincott Williams and Wilkins; ISBN: 0781718325, 2001. The organization of the genome of the influenza B virus is very similar to the organization of the genome of the influenza A virus, and the genome of the influenza C virus contains seven RNA segments and does not contain the NA gene.

The classification of influenza A viruses is carried out on the basis of the hemaglutinin (H1-H15) and neuraminidase (N1-N9) genes. In accordance with the nomenclature adopted by the World Health Organization (WHO), each strain of the virus is identified by the host animal that it infects (usually a person, unless otherwise specified); the geographic region in which it was discovered; the number of strains; year of allocation; and the antigenic properties of HA and NA. So, for example, A / Puerto Rico / 8/34 (H1N1) means strain A, isolate 8, found in humans in Puerto Rico in 1934 and having HA and NA antigens of subtype 1. In another example, A / chickens / Hong Kong / 258/97 (H5N1) means strain A, isolate 258, found in chickens in Hong Kong in 1997 and having the HA antigen of subtype 5 and the NA antigen of subtype 1. The epidemic in humans was caused by viruses having HA types H1, H2 and H3 and NA types N1 and N2.

As mentioned above, genetic changes in influenza A virus occur through two main mechanisms. Antigenic drift occurs as a result of point mutations that often occur in antigen-specific positions due to selection pressure, due to host immune responses and due to antigenic variation (also called reassortment) due to the replacement of an entire segment of the viral genome of one subtype with a segment of another subtype. Many different types of animals, including humans, pigs, birds, horses, aquatic mammals and the like, can be infected with influenza A viruses. Some influenza A viruses infect animals of specific species and usually do not infect animals of other species. However, some influenza A viruses can infect animals of several different species, mainly birds (in particular, migratory waterfowl), pigs and humans. It is believed that this property of this virus is responsible for the main antigenic variation of influenza A virus. For example, it has been suggested that a pig is infected with influenza A virus transmitted from humans and is simultaneously infected with another influenza A virus transmitted from ducks. If these two different viruses are reproduced in pig cells, the genes of the human and duck strains can “mix”, which can lead to the formation of a new virus with a unique combination of RNA segments. This process is called genetic reassortment. (It should be noted that this type of genetic reassortment is different from the change in genetic information that occurs between chromosomes during meiosis).

Influenza viruses, like other viruses and some bacterial viruses, replicate within cells. Influenza A viruses replicate in the epithelial cells of the upper respiratory tract. However, monocytes / macrophages and other white blood cells can also be infected with this virus. Many other cells with surface sialic acid glycoproteins are susceptible to in vitro infection, since the virus uses these molecules as a receptor.

Construction and selection of mRNA agents

As used herein, “disorders associated with the expression of influenza virus” means any biological or pathological condition, (1) which is mediated, at least in part, by the presence of influenza virus and (2) whose outcome is affected by a decrease in the level of influenza virus present. Specific disorders associated with influenza virus expression are provided below.

The present invention is based on the construction, synthesis and production of mRNA agents that target influenza virus genes, and on the in vitro detection of viral gene silencing in cultured cells after incubation with the mRNA agent, as well as providing protection against infection caused by influenza virus .

The mRNA agent can be appropriately designed based on sequence information and desired properties of the agent. So, for example, an mRNA agent can be designed taking into account the relative melting temperature of the candidate duplex. Typically, such a duplex should have a lower melting point at the 5'-end than at the 3'-end of the antisense chain.

The present invention relates to compositions comprising siRNA and / or kshRNA directed to one or more influenza virus transcripts. As demonstrated above in the description of the replicative cycle of the influenza virus, various types of viral RNA transcripts (primary and secondary viral RNA (vRNA), primary and secondary viral mRNA, and viral cRNA) are present in cells infected with the influenza virus, and these viral transcripts play an important role in the life cycle of the virus. Any of these transcripts are appropriate targets for siRNA-mediated inhibition by the direct or indirect mechanism described in the present invention. siRNAs and kshRNAs that target any viral mRNA transcript will specifically and directly lower the level of the transcript itself, that is, by initiating transcript degradation. In addition, as discussed below, siRNAs and cshRNAs that target certain viral transcripts (e.g. MP, PA, PB1) will cause an indirect decrease in viral transcript levels to which they are not specific. In cases where alternative splicing is possible, as in the case of mRNA encoding MP and M2, and mRNA encoding NS1 and NS2, an unspliced or spliced transcript can serve as a target transcript.

Potential viral transcripts that can serve as a target for RNAi therapy according to the invention are, for example, 1) any genomic segment of the influenza virus; 2) transcripts encoding any viral proteins, including transcripts encoding the proteins PB1, PB2, PA, NP, NS1, NS2, MP, M2, HA or NA. It should be noted that one of siRNA or kshRNA can be directed to transcripts in the form of vRNA, cRNA, and / or mRNA. However, according to Ge et al., WO 04/028471, such a viral mRNA may be the sole or primary target of RNAi.

For any specifically selected target gene, the construction of siRNA or cshRNA for use in accordance with the present invention is preferably carried out in accordance with certain criteria. Generally speaking, target sequences that are specific for a given virus (compared to sequences specific for a host) and which preferably play an important or major role in the functioning of the virus are desirable. Although some viral genes, especially genes encoding HA and NA, are characterized by a high level of mutation and are tolerant to mutations, some of their regions and / or sequences tend to remain conservative. In accordance with some variants of the invention, such sequences may be particularly suitable targets. As will be described in detail below, such conservative regions can be identified, for example, by searching the literature and / or by comparing with the gene sequences of the influenza virus available in databases, a large number of which are publicly available. In addition, in many cases, an agent delivered to a cell in accordance with the present invention may undergo one or more processing steps to form an active suppressor agent (as discussed in detail below); moreover, in such cases, for each person skilled in the art it is obvious that a suitable agent can be preferably designed so that it includes sequences that may be necessary for its processing. One aspect of the present invention is recognition, which, in the presence of multiple strains, subtypes, and the like. (referred to by the generic term variants) of existing infectious agents with varying sequences of genomes, is often desirable for the selection and / or construction of siRNAs and cshRNAs directed to regions that are highly conserved in different variants. In particular, by comparing a sufficient number of sequences and selecting highly conserved regions, it is possible to obtain many variants with one siRNA, the duplex portion of which includes such a highly conserved region. Generally speaking, the length of each region must be such that it includes the entire duplex portion of siRNA (e.g., 19 nucleotides) and optionally one or more prominent 3'-ends, although regions that are shorter than the length of a full-size duplex (e.g. 15, 16, 17 or 18 nucleotides). In accordance with some variants of the invention, the area is highly conservative for many options, if it is identical for all of these options. In accordance with some variants of the invention, the region (regardless of the length of the duplex part of siRNA, for example, 15, 16, 17, 18, or preferably 19 nucleotides) is highly conserved if it differs by at most one nucleotide (i.e., 0 or 1 nucleotide) in various variants. In accordance with some variants of the invention, such a region is highly conserved for many variants, if it differs by at most two nucleotides (i.e., 0, 1 or 2 nucleotides) in different variants. In accordance with some variants of the invention, the region is highly conserved for many variants, if it differs by at most three nucleotides (i.e., 0, 1, 2 or 3 nucleotides) for different variants. In accordance with some variants of the invention, siRNA includes a duplex part, which is directed to the region that is highly conserved in at least 5 variants, at least 15 variants, at least 20 variants, at least 25 variants, at least 30 variants, at least 40 variants, at least 50 variants or more.

In order to determine whether an area is highly conservative for a number of options, the following procedure can be performed. One member of a series of sequences is selected as the base sequence, that is, the sequence with which other sequences are compared. Typically, the length of the base sequence is the length desired for the duplex portion of siRNA, for example 15, 16, 17, 18, or preferably 19 nucleotides. In accordance with various variants of the invention, the base sequence can be any one of the sequences in the set of compared sequences, or such a sequence can be a consensus sequence derived from it, for example, selected by determining each position for each nucleotide, where this nucleotide is most often found in this position in the set of compared sequences.

After selecting a base sequence, the sequence of each member of the set of multiple options is compared with this base sequence. In order to determine whether a base sequence is highly conservative in a particular area of interest and which of its members is highly conservative, the number of differences between the base sequence and any member of a set of many options across the entire area of a given sequence is taken into account. As indicated above in various embodiments according to the invention, if the number of sequence differences between the two regions is 0; 0 or 1; 0, 1 or 2; or 0, 1, 2 or 3, it is believed that such areas are highly conserved. In positions in which such differences are present, the siRNA sequence can be chosen so that it is identical to the base sequence or one of the other sequences. Usually select the nucleotide present in the base sequence. However, in some embodiments of the invention, and in particular in those cases where the nucleotide present in a particular position in the second sequence of the compared sequence of sequences is in many compared sequences but is not in the base sequence, the siRNA sequence can be chosen so that it is identical this second sequence. In addition, in accordance with some embodiments of the invention, if the consensus nucleotide (the most common nucleotide) present at the position where differences are found differs from the nucleotide of the base sequence, a consensus nucleotide can be used. It should be noted that, as a result, a sequence can be obtained that is not identical to any of the compared sequences (since a consensus sequence can be used as a base sequence).

The authors of the present invention found that a significant number of sequences selected using the construction parameters described below (see Example 1) are effective for suppressing virus replication if they are included in siRNA or in sshRNA, as shown by the test described below.

In accordance with the results described in this application, the present invention relates to mRNA agents that reduce the level of replication of influenza virus in cultured cells infected with influenza virus and in an individual, for example a mammal, for example a human. Tables 1A-1H show representative mRNA agents directed to influenza virus. Tables 1A, C, D and E provide a list of siRNAs that do not contain nucleotide modifications, with the exception of one phosphorothioate linkage between the 3'-end and penultimate thymidines. Tables 1B and H show a list of siRNAs, where all nucleotides containing pyrimidine bases are 2'-O-methyl-modified nucleotides of the sense strand, and all uridines surrounded by 5'-ua-3 'sequences, as well as all cytidines in surrounded by 5'-ca-3 'sequences are 2'-O-methyl-modified nucleotides in the antisense strand, with the exception of mRNA agents with a duplex identified as AL-DP-2295, AL-DP-2301 and AL-DP- 2302, where all the uridines surrounded by the 5'-ug-3 'sequence are 2'-O-methyl-modified e nucleotides in the antisense strand. These latter siRNAs are not found in motifs of the 5'-ua-3 'or 5'-ca-3' sequences, and analysis of cleavage fragments after incubation of these agents in mouse serum showed that the 5'-ug-3 'sequence motif is the main site of endonucleolytic attack.

Based on these results, the present invention was developed, which, in particular, relates to an mRNA agent comprising a sense strand having at least 15 contiguous nucleotides in the sense strand sequences of the agents shown in Tables 1A-1H and an antisense strand having at least 15 contiguous nucleotides in the antisense strand sequences of the agents shown in Tables 1A-1H.

The mRNA agents shown in Tables 1A-1H consist of two chains of 19 nucleotides in length that are complementary or identical to the target sequence, and of a protruding 3'-T T- terminus. The present invention relates to agents containing at least 15, or at least 16, 17, 18 or 19 adjacent nucleotides derived from these sequences. However, although such lengths may be optimal, nevertheless, this does not mean that mRNA agents should have only such a length. One skilled in the art is well aware that shorter or longer mRNA agents may have similar efficacy, since at certain lengths, the efficiency of the nucleotide sequence will depend more on function than on the length of this nucleotide sequence. So, for example, in the work of Yang et al., PNAS 99: 9942-9947 (2002), it was demonstrated that mRNA agents have similar efficacy at sequence lengths ranging from 21 to 30 base pairs. Other researchers have found efficient gene silencing with shorter mRNA agents of up to 15 base pairs (Byrom, et al., "Inducing RNAi with siRNA Cocktails Generated by RNase III" Tech Notes 10 (1), Ambion, Inc., Austin , TX).

Therefore, to obtain an mRNA agent derived from one of the sequences shown in Tables 1A-1H, an incomplete sequence according to the invention of 15-19 nucleotides in length can be selected from the sequences shown in Tables 1A-1H. Alternatively, to one of the sequences shown in Tables 1A-1H, or to an agent containing 15 contiguous nucleotides derived from one of these agents, preferably, but not necessarily, one or more nucleotides may be added so that such added nucleotides are complementary the corresponding sequence of the target gene, for example, the influenza virus gene. For example, the first 15 nucleotides derived from one of these agents can be combined with 8 nucleotides present on the 5 ′ end of these influenza virus mRNA sequences, whereby an agent having 23 nucleotides in sense and in antisense chains. All of these derivatives of mRNA agents are included in the definition of mRNA agents according to the invention, provided that they essentially retain the ability to inhibit the replication of influenza virus in cultured human cells infected with influenza virus.

table 2 50% inhibitory concentration (IC ₅₀ ) of the selected RNAi agents shown in table 1 Duplex Designation Influenza virus target gene IC ₅₀ (nM) AL-DP-2364 PA 0.22 AL-DP-2377 PA 2.15 AL-DP-7595 PB2 0.54 AL-DP-7611 PB2 0,075 AL-DP-7617 NP 0.57 AL-DP-7622 NP 0.74 AL-DP-7633 NP ~ 90 AL-DP-7660 M 261 AL-DP-7669 M 0.79

The antisense strand of the mRNA agent must be at least 14, 15, 16, 17, 18, 19, 25, 29, 40, or 50 nucleotides in length. The specified chain should have a length equal to 60, 50, 40 or 30 nucleotides or less. The preferred length is 15-30, 17-25, 19-23 and 19-21 nucleotides.

The sense strand of the mRNA agent must have a length equal to or constituting at least 14, 15, 16, 17, 18, 19, 25, 29, 40, or 50 nucleotides. The specified chain should have a length equal to 60, 50, 40 or 30 nucleotides or less. The preferred length is 15-30, 17-25, 19-23 and 19-21 nucleotides.

The double-stranded part of the mRNA agent must have a length equal to or constituting at least 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40 or 50 pairs of nucleotides. The specified chain must have a length equal to 60, 50, 40 or 30 pairs of nucleotides or less. The preferred length is 15-30, 17-25, 19-23 and 19-21 nucleotide pairs.

Generally speaking, the mRNA agents of the invention include a region sufficiently complementary to the corresponding influenza virus gene and having a nucleotide chain length sufficient for the mRNA agent or fragment thereof to mediate inhibition of the influenza virus gene. Moreover, it is not necessary that the mRNA agent and the target gene are absolutely complementary, however, their correspondence should be such that the mRNA agent or its cleavage product can provide direct sequence-specific silencing, for example, by means of RNAi-cleavage of influenza RNA.

Therefore, mRNA agents according to the invention are agents containing a sense strand and an antisense strand, each of which has a sequence of at least 16, 17 or 18 nucleotides, which, as defined below, are essentially identical to the nucleotides of one of the sequences are presented in tables 1A-1H, with the exception of not more than 1, 2 or 3 nucleotides per chain, respectively, which were replaced by other nucleotides (for example, adenosine was replaced by uracil), where this replacement essentially does not affect the method the ability of these agents to inhibit the replication of influenza virus in cultured human cells infected with influenza virus, respectively. Therefore, such agents have at least 15 nucleotides identical to the nucleotides of one of the sequences shown in tables 1A-1H, but they either have 1, 2 or 3 mismatches compared to the sequence of the target RNA of the influenza virus, or introduced between the semantic and antisense chain. Mismatches with the sequence of the RNA target of the influenza virus, and in particular in the antisense strand, are most tolerant in the terminal regions, and if they are present, it is preferable in the terminal region or regions, for example, within 6, 5, 4 or 3 nucleotides 5'- and / or 3'-end, and most preferably, within 6, 5, 4 or 3 nucleotides at the 5'-end of the sense strand or at the 3'-end of the antisense strand. To preserve the entire double-stranded structure of the molecule, the sense chain should be sufficiently complementary only to the antisense chain.

Moreover, it is preferable that the sense and antisense strands are chosen so that the mRNA agent includes one chain or an unpaired region at one or both ends of the molecule. Thus, the mRNA agent contains sense and antisense chains, preferably paired so that they contain a protruding end, for example, one or two protruding 5'- or 3'-ends, and preferably, a protruding 3'-end containing 2-3 nucleotide. Most options have a protruding 3'-end. Preferred siRNA agents have single-stranded protruding ends, and preferably protruding 3'-ends containing 1-4 or, preferably, 2 or 3 nucleotides located at one or both ends of the specified mRNA agent. The formation of the protruding ends is due to the fact that one chain is longer than the other, or because two chains having the same length are shifted relative to each other. The unpaired nucleotides forming the protruding end may be ribonucleotides, or they may be deoxyribonucleotides, and preferably thymidine. The 5'-ends are preferably phosphorylated, or they can be non-phosphorylated.

The length of the duplex region, for example, in the siRNA agent discussed above, is preferably 15-30 nucleotides, and most preferably 18, 19, 20, 21, 22 and 23 nucleotides. The length and structure of siRNA agents can be similar to the length and structure of natural products processed by the Dicer enzyme from long dsRNAs. The present invention also includes variants in which two strands of the siRNA agent are linked, for example, by a covalent bond. The present invention also relates to “hairpin” or other single-stranded structures that form the desired double-stranded region, and preferably, a protruding 3'-end.

Evaluation of candidates for mRNA agents

As mentioned above, the present invention relates to a siRNA identification system that can be used as inhibitors of influenza virus infections and / or replication of this virus. Since, as mentioned above, kshRNAs are processed inside cells with the formation of siRNAs that have duplex parts with the same sequence as the stem structure of kshRNAs, this system can equally be used to identify siRNAs that can serve as inhibitors of infection caused by the flu virus. In this section, siRNAs are given only as an example, and this system also includes the corresponding cshRNAs. In particular, the present invention has demonstrated the successful production of siRNAs targeting viral genes to block or inhibit viral infection and / or virus replication. The methods and reagents described herein can be easily applied to construct potentially new siRNAs targeting other genes or gene regions and tested for their activity against the inhibition of influenza virus infection and / or replication of the influenza virus discussed herein. It is assumed that influenza viruses will undergo mutations and reassortments, and therefore it is necessary to continue the development and testing of new siRNAs aimed at other targets.

In various embodiments of the invention, potential influenza virus inhibitors can be tested by introducing siRNA candidate (s) into cells (for example, by exogenously introducing or by introducing a vector or construct that direct endogenous siRNA synthesis into the cell), or to laboratory animals before, during or after transfection with the genome of the influenza virus or part thereof (for example, for several minutes, hours or, at most, several days) or before, during or after infection with the influenza virus. Alternatively, potential influenza virus inhibitors can be tested by introducing siRNA candidate (s) into cells or laboratory animals that have been stably infected with the influenza virus (i.e., cells that produce viral offspring). Then, the ability of the siRNA candidate (s) to lower levels of the target transcript and / or inhibit or suppress one or more indicators or signs of the life cycle of the virus, such as virus replication, pathogenicity and / or infectivity, was evaluated. So, for example, the production of viral particles and / or the production of viral proteins and the like. can be evaluated by direct or indirect methods well known in the art.

Cells or laboratory animals to which the siRNA compositions of the invention can be delivered (test cells / animals) can be compared with similar or comparable cells or laboratory animals to which the composition of the invention was not administered (control cells / animals, e.g. cells / animals that were either not injected with siRNA, or a control siRNA, such as siRNA targeting a non-viral transcript, such as GFP) was administered. The susceptibility of the test cells / animals to the infection caused by the influenza virus can be compared with the susceptibility of the control cells / animals to such infections. The production of viral protein (s) and / or viral progeny in the test cells / animals can be compared with their production in control cells / animals. In a similar way, other indicators can be compared, such as infectivity, replication, pathogenicity of the virus, etc. In vitro standard virological tests can be performed by analysis for inhibition of viral plaques, on the cytopathic effect of the virus (CPE), on the presence of hemaglutinin or other viral proteins, on the inhibition of virus output, etc. CPE can be determined visually and by color absorption. See, for example, Sidwell, RW and Smee, D. F, "In vitro and in vivo assay systems for study of influenza virus inhibitors" Antiviral Res 2000, 48: 1. Generally speaking, the tested cells / animals and control cells / animals must be of the same species, and the tested cells must be of the same or identical type. Thus, for example, cells from the same cell line can be compared. If the cell to be tested is the primary cell, then usually the control cell should also be the primary cell. The same influenza virus strains must be used to compare the tested cells / animals with control cells / animals.

For example, the ability of a siRNA candidate to inhibit the production of influenza virus can be easily determined by (i) delivering the siRNA candidate to cells (before, during or after infection with the influenza virus); (ii) assessing the level of production of viral hemaglutinin using a hemaglutinin assay; and (iii) comparing the amount of hemaglutinin produced in the presence of siRNA with the amount produced in the absence of siRNA. (This test does not have to include a control in which siRNA is absent, but information already available on the amount of hemaglutinin produced in the absence of inhibition can be used.) A decrease in the amount of hemaglutinin clearly indicates a decrease in the level of virus production. This assay can be used to test siRNAs targeting any viral transcript, and is not limited to siRNAs targeting a transcript encoding viral hemaglutinin.

The ability of a candidate siRNA to lower a target transcript can also be assessed by determining the amount of a given target transcript using, for example, Northern blot analyzes, nuclease protection assays, reverse transcriptase PCR (RT) -PCR, RT-PCR in real time, analyzes using microarrays, etc. The ability of a candidate siRNA to inhibit the production of a polypeptide encoded by a target transcript (either at the transcriptional or post-transcriptional level) can be evaluated using a number of antibody-based methods, including, but not limited to, western blot analyzes, immunoassays, ELISA, analyzes using flow cytometry, analyzes using protein microarrays, etc. In general terms, any method for determining the amount of a target transcript or polypeptide encoded by such a target transcript can be applied.

In general terms, some preferred influenza virus inhibitors reduce the level of the target transcript by at least about 2 times, preferably at least about 4 times, more preferably at least about 8 times, at least , about 16 times, at least about 64 times or even more, compared with the level observed in the absence of an inhibitor (for example, in comparable control cells that do not contain an inhibitor). In general terms, some preferred influenza virus inhibitors inhibit the replication of the virus such that its level of replication in cells containing said inhibitor is reduced by at least about 2 times, preferably at least about 4 times, more preferably at least about 8 times, at least about 16 times, at least about 64 times, at least about 100 times, at least about 200 times, or even more, compared with the level observed in the control cells not containing such an inhibitor.

Some preferred influenza virus inhibitors inhibit virus replication to a level where production of a detectable titer of the virus is prevented for at least 24 hours, at least 36 hours, at least 48 hours, or at least 60 hours after the introduction of siRNA and infection of the cells. Some preferred influenza virus inhibitors are able to prevent (i.e., reduce to undetectable levels) or significantly reduce the level of virus replication for at least 24 hours, at least 36 hours, at least 48 hours, or at least 60 hours after siRNA administration. In accordance with various embodiments of the invention, a significant reduction in the level of virus replication means a decrease to a level of approximately less than 90%, approximately less than 75%, approximately less than 50%, approximately less than 25%, or approximately less than 10% of the level, observed in the absence of siRNA. The reduction in virus replication can be determined by any suitable method, including, but not limited to, determination of HA titer.

Test for stability, modification and re-testing of mRNA agents

A candidate mRNA agent can be evaluated for its stability, for example, for its sensitivity to cleavage with an endonuclease or exonuclease, for example, when an mRNA agent is introduced into an individual. Various methods can be used to identify areas that are sensitive to modifications, and in particular, to cleavage, for example, to cleavage by a component present in an individual’s body. Such methods can be the isolation and identification of the most common fragments formed as a result of cleavage of the candidate mRNA agent after incubation with an isolated biological medium in vitro , for example, with serum, plasma, sputum, cerebrospinal fluid or with homogenates of cells or tissues, or after contacting the individual with the candidate mRNA agent in vivo , and thereby identifying sites prone to cleavage. These and other methods are described, for example, in joint international patent application No. PCT / US2005 / 018931, filed May 27, 2005.

After identification of sites subject to cleavage, another mRNA agent having a potential cleavage site that is resistant to such cleavage can be constructed and / or synthesized, for example, by introducing a 2'-modification into the cleavage site, for example, 2'-O- methyl group. Such an additional mRNA agent can be tested again for stability, and this procedure can be repeated until it is established that the mRNA agent has the desired stability.

In vivo test

An mRNA agent identified as an agent capable of inhibiting the expression of an influenza virus gene can be tested for its in vivo functionality in an animal model (e.g., a mammal such as a mouse or rat). For example, an mRNA agent can be administered to an animal and then evaluated for its biological distribution, stability, and ability to inhibit the replication of the influenza virus or to reduce the biological or pathological processes mediated, at least in part, by the influenza virus.

The mRNA agent can be introduced directly into the desired tissue, for example, by injection, or such an mRNA agent can be introduced to the animal model in a manner analogous to the method of its introduction to humans. The mRNA agent is preferably administered to the respiratory tract of an individual, for example, intranasally.

The mRNA agent can also be evaluated for its intracellular distribution. Such an assessment may include determining the uptake of the mRNA agent by the cell. Such an assessment may also include determining the stability (e.g., half-life) of the mRNA agent. In vivo evaluation of an mRNA agent can be facilitated by using an mRNA agent conjugated to a detectable marker (e.g., a fluorescent marker such as fluorescein; a radioactive label such as ³⁵ S, ³² P, ³³ P or ³ N; gold particles or antigenic particles for immunohistochemical analysis).

The mRNA agent can be evaluated for its ability to inhibit the replication of influenza virus. In vivo influenza gene gene expression levels can be measured, for example, by in situ hybridization or by isolating RNA from tissue before or after infection with an mRNA agent. If it is necessary to kill for the collection of animal tissues, untreated animals serve as a control for comparison. Influenza virus RNA can be detected by any suitable method, including but not limited to RT-PCR, Northern blot analysis, branched DNA analysis, or RNase protection analysis. Alternatively or additionally, the expression of the influenza virus gene can be monitored by performing Western blot analysis or plaque analysis on tissue extracts treated with an mRNA agent.

Potential influenza virus inhibitors can be tested using any derived animal models. Compositions containing siRNA candidates or constructs or vectors thereof capable of regulating the synthesis of such siRNAs in a host cell or in cells that have been engineered or introduced into mutations so that they contain siRNA candidates can be administered to an animal before during or after infection with the influenza virus. The ability of such a composition to prevent a viral infection and / or to slow its development or to prevent the onset of symptoms associated with influenza virus infection and / or to alleviate the severity of animals infected with the influenza virus can be evaluated compared to animals that have not been introduced a potential virus inhibitor. flu. Such animals that serve as influenza models include, but are not limited to, non-human mice, chickens, ferrets and primates, known to those skilled in the art and commonly used to analyze the effectiveness of potential therapeutic methods and vaccines against the influenza virus. See, for example, Sidwell, R. W. & Smee, D. F, cited above. Such models may be infected with natural strains of the influenza virus and / or strains that have been modified or adapted to exist in the body of a particular host (for example, WSN or PR8 strains that have been adapted for replication in mice). The above animal models can also be used to determine the concentration necessary to achieve a specific desired effect (e.g., EC50).

The chemical structure of mRNA

The agents described herein are isolated mRNA agents, for example, dsRNA agents, which mediate RNA interference (RNAi) that inhibits the expression of the influenza virus gene.

The RNA agents discussed here are either unmodified RNAs or also RNAs that have been modified, for example, to increase efficiency; and polymers of nucleoside surrogates. Unmodified RNA is a molecule in which the components of the nucleic acid, namely sugars, bases and phosphate molecules, are the same or basically the same as in a natural molecule, and preferably the same as in the human body. Specialists in this field indicate that rare or unusual, but naturally occurring RNAs can be used as modified RNAs, see, for example, Limbach et al. Nucleic Acids Res. 22: 2183-2196, 1994. Such rare or unusual RNAs, often referred to as modified RNAs (obviously because they usually result from post-transcriptional modifications), are covered by the term “unmodified” RNA as used herein. As used herein, the term “modified RNA” means a molecule in which one or more of the components of a nucleic acid, namely, sugars, bases and phosphate molecules, are different from components present in a natural molecule, and preferably present in the human body. Although these molecules are called modified “RNAs,” however, due to their modifications, they include molecules that are not RNAs. Nucleoside surrogates are molecules in which the ribophosphate backbone is replaced by a non-ribophosphate construct, for example, uncharged mimetics of the ribophosphate backbone, which allows one to obtain bases in the “correct” spatial relationship, so that their pairing is basically similar to the pairing observed for the ribophosphate backbone. Examples of the above molecules are discussed herein.

Modifications described herein can be incorporated into any double-stranded RNA and RNA-like molecule described herein, for example an mRNA agent. It may be desirable to modify one or both of the antisense and sense strands of the mRNA agent. Since nucleic acids are polymers consisting of subunits or monomers, many of the modifications described below are present in the corresponding position and are repeated in that nucleic acid, for example, a modification of a base or a phosphate molecule or an O-unbound phosphate molecule. In some cases, this modification occurs in all the nucleic acid positions under consideration, but in many cases, and in most cases in fact, it is absent. Thus, for example, a modification can be present only at the 3'- or 5'-terminal position, only in the terminal region, for example, at the terminal nucleotide position or in the last 2, 3, 4, 5, or 10 nucleotides of the chain. The modification may be present in the double-stranded region, in the single-stranded region, or in both regions. So, for example, phosphorothioate modification in the O-unbound position can be present only at one or both ends, only in the terminal regions, for example, in the position of the terminal nucleotide, or in the last 2, 3, 4, 5, or 10 nucleotides of the chain, or in double-stranded in single-chain regions, and in particular at their ends. Similarly, a modification may be present on the sense strand, the antisense strand, or in both strands. In some cases, the sense and antisense chains have the same modifications or modifications of the same class, and in other cases the sense and antisense chains have different modifications, for example, in some cases it may be desirable to modify only one chain, for example, the sense chain.

The two main goals of introducing modifications to mRNA agents are to protect them from degradation in biological media and to improve their pharmacological properties, for example pharmacological properties, which are discussed in detail below. Other suitable modifications to the sugar, base or backbone of the mRNA agent are described in PCT Joint Application No. PCT / US2004 / 01193, filed January 16, 2004. The mRNA agent may include non-natural bases, such as those described in PCT Joint Application No. PCT / US2004 / 011822, filed April 16, 2004, an mRNA agent may include a non-natural sugar, such as a molecule bearing a non-carbohydrate cyclic group. Representative signs of unnatural sugars used in mRNA agents are described in PCT Joint Application PCT / US2004 / 11829, filed April 16, 2003.

The mRNA agent may include an internucleotide linkage (e.g., a chiral phosphorothioate linkage) used to increase nuclease resistance. Additionally or alternatively, the mRNA agent may include a ribose mimetic used to increase nuclease resistance. Representative internucleotide bonds and ribose mimetics used to increase nuclease resistance are described in PCT Joint Application No. PCT / US2004 / 07070, filed March 8, 2004.

The mRNA agent may include ligand conjugated monomeric subunits and monomers for the synthesis of oligonucleotides. Representative monomers are described in joint application for US patent No. 10/916185, filed August 10, 2004

The mRNA agent may have a ZXY structure, for example, the structure described in PCT Joint Application No. PCT / US2004 / 07070, filed March 8, 2004.

The mRNA agent can form a complex with an amphipathic group. Representative examples of amphipathic groups used in mRNA agents are described in PCT Joint Application PCT / US2004 / 07070, filed March 8, 2004.

In another embodiment of the invention, the mRNA agent may complex with a delivery agent that has a modular complex. Such a complex may include a carrier agent associated with one or more of the following components (preferably two or more, and more preferably three components), such as (a) a condensing agent (for example, an agent capable of attaching a nucleic acid, for example, to bind to a nucleic acid, for example, through ionic or electrostatic interactions); (b) a fusogenic agent (for example, an agent capable of binding to the cell membrane and / or transported through the cell membrane); and (c) a targeting group, for example, an agent delivered to a cell or tissue, for example a lectin, glycoprotein, lipid or protein, for example an antibody that binds to a cell of a particular type. mRNA agents that form complexes with the delivery agent are described in PCT Joint Application No. PCT / US2004 / 07070, filed March 8, 2004.

An mRNA agent may have non-canonical pairs, such as pairs between sense and antisense sequences of an mRNA duplex. Representative examples of noncanonical mRNA agents are described in PCT Joint Application No. PCT / US2004 / 07070, filed March 8, 2004.

Increased Nuclease Resistance

An mRNA agent, for example an mRNA agent that targets the influenza virus, may have an increased level of resistance to nucleases.

One way to increase the level of resistance is the identification of cleavage sites and the modification of such sites to inhibit cleavage, described in joint application for US patent No. 60/559917, filed May 4, 2004. Thus, for example, 5'- dinucleotides can serve as cleavage sites. ua-3 ', 5'-ca-3', 5'-ug-3 ', 5'-uu-3' or 5'-cc-3 '. In some embodiments of the invention, all the pyrimidines of the mRNA agent carry a 2'-modification either in the sense strand, or in the antisense strand, or in both strands, and therefore the mRNA agent has increased resistance to endonucleases. Increased resistance in nuclease can also be achieved by modifying the 5'-nucleotide, resulting in, for example, at least one 5'-uridine-adenine-3 '(5'-ua-3') dinucleotide, wherein said uridine is a 2'-modified nucleotide; at least one 5'-cytidine-adenine-3 '(5'-ca-3') - dinucleotide, where 5'-cytidine is a 2'-modified nucleotide; at least one 5'-uridine-guanine-3 '(5'-ug-3') is a dinucleotide, where 5'-uridine is a 2'-modified nucleotide; at least one 5'-uridine-uridin-3 '(5'-uu-3') is a dinucleotide, where 5'-uridine is a 2'-modified nucleotide; or at least one 5'-cytidine-cytidin-3 '(5'-cc-3') is a dinucleotide, where 5'-cytidine is a 2'-modified nucleotide described in joint international application No. PCT / US2005 / 018931, filed May 27, 2005, an mRNA agent may include at least 2, at least 3, at least 4, or at least 5 such dinucleotides. In a particularly preferred embodiment of the invention, the 5'-nucleotide in all motifs of the 5'-ua-3 'and 5'-ca-3' sequence, either in the sense strand, in the antisense strand, or in both strands, is a modified nucleotide. Preferably, the 5'-nucleotide in all motifs of the 5'-ua-3 ', 5'-ca-3' and 5'-ug-3 'sequence, either in the sense strand, in the antisense strand, or in both strands is a modified nucleotide. More preferably, all pyrimidine nucleotides in the sense strand are modified nucleotides, and 5'-nucleotides in all motifs of the 5'-ua-3 'and 5'-ca-3' sequences in the antisense strand are modified nucleotides, or the antisense strand is not contains neither 5'-ua-3 'nor 5'-ca-3', but in all cases contains 5'-ug-3 '.

Preferably, the 2'-modified nucleotides include, for example, a 2'-modified ribose unit, for example, the 2'-hydroxyl group (OH) can be modified or replaced by a number of different “oxy” or “deoxy” substituents.

Examples of “hydroxy” -2′-modifications of the hydroxyl group are alkoxy or aryloxy (OR, for example, R = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar); polyethylene glycols (PEG), O (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OR; “blocked” nucleic acids (LNAs) in which the 2'-hydroxyl is linked, for example, by a methylene bridge, to the 4'-carbon of the same ribose sugar; O-amine and aminoalkoxy, O (CH ₂ ) _n amine (for example, amine = NH ₂ ; alkylamino, dialkylamino, heterocyclylamino, arylamino, diarylamino, heteroarylamino or diheteroarylamino, ethylenediamine, polyamino). It should be noted that oligonucleotides containing only a methoxyethyl group (MOE), (OCH ₂ CH ₂ OCH ₃ , PEG derivative) possess nuclease stability, in contrast to oligonucleotides modified only with phosphorothioate groups.

“Deoxy” modifications are hydrogen (that is, deoxyribose sugars that are especially suitable for protruding regions of incomplete dsRNA); halogen (e.g. fluorine); amino (e.g. NH ₂ ; alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, diheteroarylamino or amino acid); NH (CH ₂ CH ₂ NH) _n CH ₂ CH ₂ -amine (amine = NH ₂ ; alkylamino, dialkylamino, heterocyclylamino, arylamino, diarylamino, heteroarylamino or diheteroarylamino); -NHC (O) R (R = R alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), cyano; mercapto; alk ylthioalkyl; thioalkoxy; and alkyl, cycloalkyl, aryl, alkenyl and alkynyl, which may be substituted, for example, but not necessarily, with a functional amino group.

Preferred substituents are 2'-methoxyethyl, 2'-OCH ₃ , 2'-O-allyl, 2'-C-allyl and 2'-fluoro.

The incorporation of furanose sugars into the oligonucleotide backbone can also lead to a decrease in the level of endonucleotic cleavage. The mRNA agent can then be modified by the inclusion of a 3'-cationic group or by inverting the nucleoside at the 3'-end with a 3'-3'-bond. In another alternative, the 3'-end may be blocked by an aminoalkyl group, for example 3'-C5-aminoalkyl-dT. Other 3'-conjugates can inhibit 3'-5'-exonucleolytic cleavage. Not limited to any theory, it can only be noted that a 3'-conjugate, such as naproxen or ibuprofen, can inhibit exonucleolytic cleavage by sterically blocking the binding of exonuclease to the 3'-end of the oligonucleotide. 3'-5'-exonucleases can be blocked even by small alkyl chains, aryl groups or heterocyclic conjugates or modified sugars (D-ribose, deoxyribose, glucose, etc.).

Nucleolytic cleavage can also be inhibited by the introduction of modifications into the phosphate linker, for example phosphorothioate bonds. Thus, preferred mRNA agents are pure nucleotide dimers or nucleotide dimers enriched in a particular chiral form of a modified phosphate group containing a heteroatom in a non-bridging position, usually occupied by oxygen. Such a heteroatom may be S, Se, Nr ₂ or Br ₃ . If the heteroatom is S, then the preferred bond is an enriched or chiral pure Sp bond. The term “enriched” refers to a form that is at least 70, 80, 90, 95, or 99% of the preferred form. Modified phosphate bonds are particularly effective for inhibiting exonucleolytic cleavage when introduced near the 5'- or 3'-terminal positions, and preferably the 5'-terminal positions of the mRNA agent.

5'-conjugates can also inhibit 5'-3'-exonucleolytic cleavage. Not limited to any theory, it can only be noted that a 5'-conjugate, such as naproxen or ibuprofen, can inhibit exonucleolytic cleavage by sterically blocking the binding of exonuclease to the 5'-end of the oligonucleotide. 3'-5'-exonucleases can be blocked even by small alkyl chains, aryl groups or heterocyclic conjugates or modified sugars (D-ribose, deoxyribose, glucose, etc.).

An mRNA agent may have increased resistance to nucleases if the duplex mRNA agent comprises a single stranded nucleotide protruding from at least one end. In preferred embodiments, the protruding nucleotides comprise 1-4, and preferably 2-3, unpaired nucleotides. In a preferred embodiment of the invention, such an unpaired single-stranded protruding end nucleotide that is adjacent to the terminal nucleotide pair contains a purine base and the terminal nucleotide pair is a G-C pair, or at least two of the last four complementary nucleotide pairs are G-C pairs. In other embodiments, the nucleotide protruding end may have 1 or 2 unpaired nucleotides, and in a representative embodiment of the invention, such nucleotide protruding end is 5'-gc-3 '. In preferred embodiments of the invention, the protruding nucleotide is at the 3 ′ end of the antisense strand. In one embodiment, the mRNA agent includes a 5'-cgc-3 'motif at the 3'-end of the antisense strand, resulting in a protruding end of two nucleotides, 5'-gc-3'.

Thus, an mRNA agent may include modifications that promote inhibition of cleavage, for example, by nucleases, for example endonucleases or exonucleases present in an individual. Such monomers are referred to herein as NRMs or monomers promoting nuclease resistance, and corresponding modifications are denoted by NRM modifications. In many cases, such modifications can also modulate other properties of the mRNA agent, for example, the ability to interact with a protein, for example with a transport protein, for example with serum albumin or with a member of RISC, or the ability of the first and second sequences to duplex with each other or with another sequence, for example with a target molecule.

One or more different NRM modifications may be introduced into the mRNA agent or into the sequence of the mRNA agent. The NRM modification may be used in such an mRNA agent sequence or in an mRNA agent more than once.

NRM modifications include some modifications that may be present only at the ends, and other modifications that may be present in any position. Some NRM modifications can inhibit hybridization, and therefore it is preferable to use them only in the terminal regions, and preferably not to use them in the cleavage site or in the cleavage region of a sequence that is directed to the considered sequence or gene, in particular to the antisense strand. These modifications can be used in any position of the sense strand, provided that between the two chains of the ds-mRNA agent a sufficient level of hybridization will be maintained. In some embodiments of the invention, it is desirable to introduce NRM at the cleavage site or at the cleavage site of the sense strand, as this can minimize unwanted silencing.

In most cases, NRM modifications will be distributed depending on whether they are present on the sense or on the antisense chain. If modifications are present on the antisense strand, modifications that suppress or inhibit endonuclease cleavage should not be inserted in the region subjected to RISC-mediated cleavage, for example, in the cleavage site or in the cleavage region (as described in Elbashir et al., 2001, Genes and Dev. 15: 188, which is incorporated herein by reference). Cleavage of the target occurs approximately in the middle of the antisense strand consisting of 20 or 21 nucleotides, or at positions 10 or 11 nucleotides located above the first nucleotide on the target mRNA, which is a complementary antisense strand. As used herein, the term “cleavage site” means nucleotides located on either side of the cleavage site, on a target, or on an mRNA agent chain that hybridizes to that target. The term “cleavage region” means a cleavage site consisting of 1, 2 or 3 nucleotides located in any direction.

Such modifications may be introduced at the end regions, for example at the end position or at positions 2, 3, 4 or 5 from the end of the sense or antisense chain.

Related Ligands

The properties of the mRNA agent, including its pharmacological properties, can be changed and modulated, for example, by introducing ligands, for example, bound ligands. In addition, the pharmacological properties of the mRNA agent can be improved by introducing a ligand into the composition of the mRNA agent in the event that such mRNA agent contains a bound ligand.

Molecules of a wide range, for example ligands, can be associated with an mRNA agent, or they can be used as a conjugate preparation or as an additive, attached, for example, to a carrier, that is, to a ligand-conjugated monomeric subunit. Examples of such molecules are described below in the discussion of the ligand-conjugated monomeric subunit, however, these molecules are only preferred and may be linked to the mRNA agent in other regions.

Preferred molecules are ligands that are bound to the carrier, preferably covalently, either directly or indirectly via an internal bond. In a preferred embodiment of the invention, the ligand is bound to the carrier via an internal bond. A ligand or a bound ligand may be present on the ligand conjugated monomer if such a ligand conjugated monomer is included in the growing chain. In some embodiments of the invention, this ligand can be introduced into the ligand-conjugated precursor monomeric subunit after incorporating such a ligand-conjugated precursor monomeric subunit into the growing chain. So, for example, a monomer having, for example, an amino-terminal bond, for example TAP- (CH ₂ ) _n NH ₂ , can be included in a growing sense or antisense chain. In a subsequent operation, that is, after the monomeric precursor subunit is inserted into the chain, a ligand having an electrophilic group, for example a pentafluorophenyl ether group or an aldehyde group, can then be attached to the ligand-conjugated precursor monomer by reacting the electrophilic group of the ligand with the terminal nucleophilic group subunit linkage of the ligand conjugated precursor monomer.

In preferred embodiments of the invention, the ligand after its incorporation into the mRNA agent affects the nature of the distribution, the targeting properties, or the lifetime of the mRNA agent. In preferred embodiments of the invention, the ligand provides increased affinity for a selected target, for example, a molecule, cell or cell type, to a compartment, such as a compartment of a cell or organ, tissue, organ or region of an organism, compared to variants in which this ligand is absent.

Preferred ligands can enhance transport, hybridization and specificity, and they can also increase the nuclease resistance of the resulting natural or modified oligoribonucleotide or polymer molecule containing any combination of the monomers described herein and / or natural or modified ribonucleotides.

Generally speaking, ligands can include therapeutic modifiers, for example, to increase the level of absorption; diagnostic compounds or reporter groups, for example, to monitor the nature of the distribution; cross-linking agents; molecules that report resistance to nuclease, and natural or rarely found nucleotide bases. The main examples are lipophilic molecules, lipids, lectins, steroids (e.g. uvol, hecigenin, diosgenin), terpenes (e.g. triterpenes, e.g. sarsasapogenin, Fridelin, lithocholic acid, derivatized with epifridelanol), vitamins, carbohydrates (e.g. Dextlan, , chitosan, inulin, cyclodextrin or hyaluronic acid), proteins, protein-binding agents, integrin-targeting molecules, polycations, peptides, polyamines and peptidomimetics.

The ligand may be a natural or recombinant or synthetic molecule, such as a synthetic polymer, for example a synthetic polyamino acid. Examples of polyamino acids are polylysine (PLL), poly-L-aspartic acid, poly-L-glutamic acid, a copolymer of styrene and maleic anhydride, a copolymer of L-lactide and glycolide, a copolymer of divinyl ether and maleic anhydride, a copolymer of N- (2- hydroxypropyl) methacrylamide (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly (2-ethyl acrylic acid), N-isopropyl acrylamide polymers or polyphosphazine. Examples of polyamines are polyethyleneimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, polyamine-peptidomimetic, polyamine-dendrimer, arginine, amidine, protamine, cationic molecules, for example, cationic lipid, cationic porphyrin, quaternary polyamine salt helical peptide.

Ligands can also be targeting groups, for example, an agent for delivery to the cell or tissue, for example thyrotropin, melanotropin, surface-active protein A, carbohydrate mucin, glycosylated polyamino acid, transferrin, bisphosphonate, polyglutamate, polyaspartate or RGD peptide or RGD peptidomimetic.

Ligands can be proteins, for example, glycoproteins, lipoproteins, for example low density lipoprotein (LDL) or albumin, for example human serum albumin (HSA), or peptides, for example molecules with specific affinity for the co-ligand, or antibodies, for example, an antibody that binds to a cell of a particular type, such as a cancer cell, endothelial cell or osteocyte. Hormones and hormone receptors can also be ligands. They may also include non-peptide moieties such as cofactors, polyvalent lactose, polyvalent galactose, N-acetyl-galactosamine, N-acetyl-glucosamine, polyvalent mannose or polyvalent fucose. The ligand may be, for example, a lipopolysaccharide, p38 MAP kinase activator, or NF-kB activator.

The ligand can be a substance, for example, a medicine, which can stimulate the penetration of an mRNA agent into a cell, for example, by disruption of the cell cytoskeleton, for example, by disruption of microtubules, microfibers and / or intermediate cell filaments. The medicament may be, for example, taxon, vincristine, vinblastine, cytochalazine, nocodazole, yaplacinolide, latrunculin A, phalloidin, swine solid A, indanocin or myoservin.

In one aspect of the invention, the ligand is a lipid or lipid-containing molecule. Such a lipid or lipid-containing molecule preferably binds to a whey protein, for example human serum albumin (HSA). The HSA-binding ligand provides the distribution of this conjugate in the target tissue, for example in the liver tissue, including liver parenchyma cells. Other molecules that bind to HSA can also be used as ligands. So, for example, neproxin or aspirin can be used. A lipid or lipid-containing ligand can (a) increase the resistance to conjugate cleavage, (b) increase the ability to target or transport the conjugate to a target cell or cell membrane and / or (c) can be used to regulate binding to serum protein, for example with HSA.

The lipid ligand can be used to modulate, for example, to regulate the level of binding of the conjugate to the target tissue. So, for example, a lipid or lipid ligand, which is more strongly associated with HSA, is less likely to target the kidneys, and therefore it is less likely that it will be excreted from the body. A lipid or lipid ligand, which is less strongly associated with HSA, can be used to deliver the conjugate to the kidneys.

In a preferred embodiment of the invention, said lipid ligand binds to HSA. Moreover, it is preferable that it binds to HSA with an affinity sufficient for such a conjugate to be distributed predominantly in non-renal tissue. However, it is preferred that the affinity is not so strong that such a binding of HSA to the ligand is irreversible.

In another aspect of the invention, said ligand is a molecule, such as a vitamin or trace element, that is absorbed by a target cell, such as a proliferating cell. These molecules are particularly suitable for treating disorders characterized by undesired cell proliferation, for example, malignant or non-cancerous cells, for example cancer cells. Representative vitamins are vitamin A, E, and K. Other representative vitamins are vitamins B, for example folic acid, B12, riboflavin, biotin, pyridoxal, or other vitamins or trace elements absorbed by cancer cells.

In another aspect of the invention, said ligand is an agent capable of penetrating into cells, and preferably an agent with a helical structure, penetrating into cells. An amphipathic agent is preferred. A representative agent is a peptide such as tat or an antennae peptide (antennapedia) peptide. If the agent is a peptide, then it can be modified, and such peptides are peptides, including peptidyl mimetics, inverters, non-peptide or pseudopeptide bonds, and may contain D-amino acids. Such a spiral agent is preferably an agent that has an alpha-helical structure, and preferably contains a lipophilic and lipophobic phase.

5'-phosphate modifications

In preferred embodiments of the invention, the mRNA agents are 5'-phosphorylated agents or agents comprising a phosphoryl analogue at the 5'-end. 5'-phosphate antisense strand modifications are those compatible with RISC-mediated gene silencing. Suitable modifications are 5'-monophosphate ((HO) 2 (O) P-O-5 '); 5'-diphosphate ((HO) 2 (O) P-O-P (HO) (O) -O-5 '); 5'-triphosphate ((HO) 2 (O) P-O- (HO) (O) P-O-P (HO) (O) -O-5 '); 5'-guanosine cap (7-methylated or unmethylated) (7m-G-O-5 '- (HO) (O) P-O- (HO) (O) P-O-P (HO) (O) -O-5'); 5'-adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (NO-5 '- (HO) (O) PO- (HO) (O) POP (HO) (O) -O-5') ; 5'-monothiophosphate (phosphorothioate; (HO) 2 (S) P-O-5 '); 5'-monodithiophosphate (phosphordithioate; (HO) (HS) (S) P-O-5 '), 5'-phosphorothiolate ((HO) 2 (O) P-S-5'); any additional combination of monophosphate, diphosphate and triphosphate in which the oxygen atom is replaced by a sulfur atom (e.g. 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'-phosphoramidates ((HO) 2 (O ) P-NH-5 ', (HO) (NH2) (O) PO-5'), 5'-alkylphosphonates (R = alkyl = methyl, ethyl, isopropyl, propyl and the like, e.g. RP (OH) (O) -O-5'-, (OH) 2 (O) P-5'-CH2-), 5'-alkyl ester of phosphoric acid (R = alkyl ester = methoxymethyl (MeOCH2-), ethoxymethyl, etc. ., for example RP (OH) (O) -O-5'-).

The sense strand can be modified to inactivate it and to prevent the formation of active RISC and, thus, the possible reduction of undesirable effects. This can be achieved through a modification that prevents the 5'-phosphorylation of the sense strand, for example by modification with a 5'-O-methylribonucleotide (see Nykänen et al., (2001) ATP requirements and small interfering RNA structure in the RNA interference pathway. Cell 107, 309-321). Other modifications that prevent phosphorylation can also be used, for example, the simple substitution of 5'-OH with an H atom rather than OMe. Alternatively, a large bulky group can be attached to the 5'-phosphate, as a result of which it turns into a phosphodiester bond.

Unnatural nucleotide bases

Nitropyrrolyl and nitroindolyl are non-natural nucleotide bases that are members of a class of compounds known as universal bases. Universal bases are compounds in which any of the four natural bases can be replaced without any significant effect on the nature of the melting or activity of the oligonucleotide duplex. It was suggested that, in contrast to stabilizing hydrogen bonds associated with natural nucleotide bases, oligonucleotide duplexes containing 3-nitropyrrolyl nucleotide bases are stabilized only through stacking interactions. The absence of significant interaction of hydrogen bonds with nitropyrrolyl nucleotide bases allows to eliminate specificity for a specific complementary base. In addition, it has been confirmed in various studies that 4-, 5- and 6-nitroindolyl has very little specificity for four natural bases. It is interesting to note that the oligonucleotide duplex containing 5-nitroindolyl is more stable than the corresponding oligonucleotides containing 4-nitroindolyl and 6-nitroindolyl. Procedures for the preparation of 1- (2'-O-methyl-β-D-ribofuranosyl) -5-nitroindole are described by Gaubert, G .; Wengel, J. Tetrahedron Letters 2004, 45, 5629. Other universal bases suitable for use in the present invention are hypoxanthinyl, isoinosinyl, 2-azainosinyl, 7-deazainosinyl, nitroimidazolyl, nitropyrazolyl, nitrobenzimidazolyl, nitroindiroindiolazole derivatives. A more detailed discussion, including procedures for the synthesis of nitropyrrolyl, nitroindolyl, and other universal bases mentioned above, can be found in Vallone et al., Nucleic Acids Research, 27 (17): 3589-3596 (1999); Loakes et al., J. Mol. Bio., 270: 426-436 (1997); Loakes et al., Nucleic Acids Research, 22 (20): 4039-4043 (1994); Oliver et al. Organic Letters, Vol. 3 (13): 1977-1980 (2001); Amosova et al., Nucleic Acids Research, 25 (10): 1930-1934 (1997); Loakes et al., Nucleic Acids Research, 29 (12): 2437-2447 (2001); Bergstrom et al., J. Am. Chem. Soc., 117: 1201-1209 (1995); Franchetti et al., Biorg. Med. Chem. Lett. 11: 67-69 (2001); and Nair et al., Nucleosides, Nucleotides & Nucleic Acids, 20 (4-7): 735-738 (2001).

Difluorotolyl is a non-natural nucleotide base that acts as a universal base. Difluorotolyl is an isoster of the natural nucleotide base of thymine. But difluorotolyl, unlike thymine, does not show appreciable selectivity to any of the natural bases. Other aromatic compounds that act as universal bases and can be used in the present invention are 4-fluoro-6-methylbenzimidazole and 4-methylbenzimidazole. In addition, the relatively universal hydrophobic isocarbostyryl derivatives, such as 3-methylisocarbostyryl, 5-methylisocarbostyryl and 3-methyl-7-methyl-isocarbyl, are universal bases that cause only a slight destabilization of oligonucleotide duplexes compared to the oligonucleotide sequence containing only natural bases. Other unnatural nucleotide bases contemplated by the present invention are 7-azaindolyl, 6-methyl-7-azainindolyl, imidazopyridinyl, 9-methylimidazopyridinyl, pyrrolpyrinyl, isocarbostyryl, 7-propynylisocarbostyryl, propynyl-7-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-azyl-n-azyl-n-azyl-azyl-n-azyl-n-azyl-n-azyl-n-azyl-n-azyl-n-azyl-n-azyl-n-l-azyl-azyl-n-azyl-n-azyl-n-azyl-n-alkyl-n-with-nyl-n-azonyl-di-azonyl-with-di-azonyl-with-alkylene - n-with-alkonyl - with naryl with naphtha. , 4-methylindolyl, 4,6-dimethylindolyl, phenyl, naphthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenyl, tetracenyl, pentacenyl and their structural derivatives. A more detailed discussion, including procedures for the synthesis of difluorotolyl, 4-fluoro-6-methylbenzimidazole, 4-methylbenzimidazole and the other non-natural bases mentioned above, can be found in Schweitzer et al., J. Org. Chem., 59: 7238-7242 (1994); Berger et al., Nucleic Acids Research, 28 (15): 2911-2914 (2000); Moran et al., J. Am. Chem. Soc., 119: 2056-2057 (1997); Morales et al., J. Am. Chem. Soc., 121: 2323-2324 (1999); Guckian et al., J. Am. Chem. Soc. 118: 8182-8183 (1996); Morales et al., J. Am. Chem. Soc., 122 (6): 1001-1007 (2000); McMinn et al., J. Am. Chem. Soc., 121: 11585-11586 (1999); Guckian et al., J. Org. Chem., 63: 9652-9656 (1998); Moran et al., Proc. Natl. Acad. Sci., 94: 10506-10511 (1997); Das et al., J. Chem. Soc., Perkin Trans., 1: 197-206 (2002); Shibata et al., J. Chem. Soc., Perkin Trans., 1: 1605-1611 (2001); Wu et al., J. Am. Chem. Soc. 122 (32): 7621-7632 (2000); O'Neill et al., J. Org. Chem., 67: 5869-5875 (2002); Chaudhuri et al., J. Am. Chem. Soc., 117: 10434-10442 (1995); and in US patent No. 6218108.

A more detailed description of the synthesis and application of universal bases is given in the joint and simultaneously pending application PCT / US2005 / 025967, filed July 21, 2005, which in its entirety is incorporated into this description by reference.

The use of universal bases can be especially useful in cases where the target gene is located in a microorganism that exhibits variability between different strains of this microorganism. This often applies even to areas of the viral genome that are considered highly conserved. The introduction of a universal base allows one to obtain mRNA agents that target a large number of different strains of the virus, even if they differ in one or several, for example, in three positions of the nucleotides.

The best universal bases are those included in the region of the mRNA agent, which is at least sensitive to nucleotide mismatches regarding the specificity and activity of the mRNA agent. It was shown that positions 2–9 of the antisense strand of the mRNA agent are the most susceptible to mismatches between the antisense strand and the target mRNA, and this region is called the “unique region” (seed region (“grain” region) of the mRNA agent. Therefore, when one or more universal bases are introduced into an mRNA agent, this (s) base (s) is preferably introduced at positions outside this unique area.

Table 1F and table 1G show mRNA agents containing universal bases in mutually complementary positions in the sense and antisense strands. Although this option is one of the preferred variants of the mRNA agents according to the invention, the effect of the universal base in the mRNA agent is more pronounced if this universal base is present in the antisense strand. Therefore, it is obvious that the base in the sense strand in the position in which it paired with the universal base in the antisense strand can be either a universal base or any other suitable base, such as a, u, c or g. It is desirable to determine which base in this position of the sense strand will have the highest activity and / or selectivity for a given mRNA agent. Alternatively, a base can be selected that is present at this particular position in most variants of the target genes, the expression of which must be inhibited by the mRNA agent in question.

Transport of mRNA agents into cells

Not limited to any particular theory, it should be noted that chemical similarities between cholesterol-conjugated mRNA agents and certain components of lipoproteins (e.g., cholesterol, cholesterol esters, phospholipids) can lead to the binding of mRNA agents to lipoproteins (e.g., LDL, HDL ) in the blood and / or to the interaction of the mRNA agent with cellular components with affinity for cholesterol, for example, components of the cholesterol transport pathway. Lipoproteins, as well as their components, are absorbed and processed by cells under the influence of various mechanisms of active and passive transport, for example, such as, but not limited to, endocytosis of the LDL receptor associated with LDL; endocytosis of oxidized or otherwise modified LDL through interaction with acceptor receptor A; the absorption of HDL cholesterol by the liver, mediated by the acceptor receptor B1; pinocytosis or cholesterol transport through membranes by the action of ABC transporter proteins (ATP-binding cluster), for example ABC-A1, ABC-G1 or ABC-G4. Therefore, cholesterol conjugated mRNA agents can be readily absorbed by cells possessing such transport mechanisms, for example, liver cells. In general, the present invention relates to specific and general methods for delivering mRNA agents to cells expressing certain components of a cell surface, for example, receptors, by conjugating a natural ligand for such a component (e.g., cholesterol) with an mRNA agent or by conjugating a chemical molecule (e.g. , cholesterol) with an mRNA agent that interacts or binds to a natural ligand for such a component (e.g., LDL, HDL).

Other embodiments of the invention

RNA, such as an mRNA agent, can be produced in a cell in vivo , for example, from exogenous DNA matrices delivered to that cell. For example, DNA templates can be inserted into vectors and used as vectors for gene therapy. Gene therapy vectors can be delivered to an individual, for example, by intravenous injection, local injection (US Pat. No. 5,328,470) or by stereotactic injection (see, for example, Chen et al. Proc. Natl. Acad. Sci. USA 91: 3054-3057 , 1994). The pharmaceutical preparation of a gene therapy vector may include a gene therapy vector in a suitable diluent, or it may include a slow release matrix that includes a gene delivery vehicle. DNA matrices, for example, can include two transcription units, one of which produces a transcript including the upper chain of the mRNA agent, and the other produces a transcript that includes the lower chain of the mRNA agent. After transcription of the matrices, an mRNA agent is produced, which is then processed into fragments of the siRNA agent that mediate gene silencing.

Songs

The present invention also includes pharmaceutical compositions and preparations containing dsRNA compounds according to the invention. The pharmaceutical compositions according to the invention can be administered in various ways depending on the desired course of treatment, that is, local or systemic, and on the site of the body being treated. The introduction may be local administration, intrapulmonary administration, for example, by inhalation or insufflation of powders or aerosols, including administration by aerosol spray; intratracheal administration, intranasal administration, epidermal administration and transdermal administration, as well as oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, for example, intrathecal or intraventricular administration.

Topical pharmaceutical compositions and preparations may be transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Necessary or desirable may be standard pharmaceutical carriers, aqueous, powder or oil bases, thickeners, and the like. Condoms and coated gloves and the like can also be used. Preferred topical preparations are those in which the dsRNA of the invention is a mixture with topical delivery agents such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes are neutral (e.g., dioleoylphosphatidylethanolamine = DOPE, dimyristoylphosphatidylcholine = DMPC, distearoylphosphatidylcholine), negatively charged (e.g., dimyristoylphosphatidylglycerol = DMPG) and cationic (e.g., dioleoiltetrametilaminopropil = DOTAP and dioleoylphosphatidylethanolamine = DOTMA). The dsRNAs of the invention can be encapsulated in liposomes or they can form complexes with liposomes, and in particular with cationogenic liposomes. Alternatively, dsRNAs can form complexes with lipids, and in particular with cationic lipids. Preferred fatty acids and fatty acid esters include, but are not limited to, arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate , monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitine, atsilholin or C _1-10 alkyl ester (e.g., isopropyl myristate, IPM), monoglyceride, diglyceride or pharmacist Eski acceptable salts. Preparations for local administration are described in detail in the application for US patent, reg. No. 09/315298, filed May 20, 1999, which in its entirety is introduced into the present description by reference.

Compositions and preparations for oral administration are powders or granules, microparticles, nanoparticles, suspensions or solutions in water or in anhydrous environments, capsules, gel capsules, sachets, tablets or mini-tablets. For their preparation, it may be desirable to use thickeners, flavors, diluents, emulsifiers, dispersants or binders. Preferred oral preparations are those in which the dsRNA of the invention is administered in combination with one or more penetration enhancers, surfactants, and chelating agents. Preferred surfactants are fatty acids and / or their esters or salts, bile acids and / or their salts. Preferred bile acids / salts are chenodeoxycholic acid (CDCA) and ursodeoxychienodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucocholic acid, glycocholic acid, glycodeoxycholic acid, taurochlorohydric acid, taurohydrocholic acid, taurohydrochloric acid, taurohydrochloric acid, taurohydrochloric acid, taurohydrochloride acid and sodium glycodihydrofusidate. Preferred fatty acids are arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin-1 glycerol, glycerol , 1-dodecylazacycloheptan-2-one, acylcarnitine, acylcholine or monoglyceride, diglyceride or their pharmaceutically acceptable salts (e.g. sodium salts). Also preferred are combinations of permeation enhancers, for example fatty acids / salts in combination with bile acids / salts. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Other permeation enhancers are polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. The dsRNAs according to the invention can be administered orally, in the form of granules including finely divided dry particles, or in the form of a complex with micro- or nanoparticles. The agents that form complexes with dsRNA are polyamino acids; polyimines; polyacrylates; polyalkyl acrylates, polyoxethanes, polyalkyl cyanoacrylates; cationized gelatins, albumin, starches, acrylates, polyethylene glycols (PEGs) and starches; polyalkyl cyanoacrylates; DEAE-derivatized polyimines, pullulans, celluloses and starches. Particularly preferred complexing agents are chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythioethylaminomethylene P (TDAE), polyaminostyrene (e.g. p-amino), poly (methylcyanoacrylate) ), poly (butylcyanoacrylate), poly (isobutylcyanoacrylate), poly (isohexylcyanoacrylate), DEAE-methacrylate, DEAE-hexyl acrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethyl acrylate, polyhexyl acid, , DL-milk and hl copolymer glycolic acid (PLGA), alginate and polyethylene glycol (PEG). Preparations for the oral administration of dsRNA and their preparation are described in detail in US patent applications reg. No. 08/886829 (filed July 1, 1997), reg. No. 09/108673 (filed July 1, 1998), reg. No. 09/256515 (filed February 23, 1999), reg. No. 09/082624 (filed May 21, 1998) and reg. No. 09/315298 (filed May 20, 1999), each of which in its entirety is incorporated into this description by reference.

Compositions and preparations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions, which may also contain buffers, diluents and other suitable additives, such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions of the invention may include, but are not limited to, solutions, emulsions and preparations containing liposomes. These compositions can be prepared from various components, which are, but are not limited to, liquid samples, self-emulsifying solids and self-emulsifying semi-solid substances.

The pharmaceutical preparations of the invention, which can usually be in a unit dosage form, can be prepared by standard methods well known to pharmacists. Such methods include the step of mixing the active ingredients with pharmaceutically acceptable carrier (s) and excipient (s). In general terms, such preparations are prepared by uniformly and thoroughly mixing the active ingredients with liquid carriers and with finely divided solid carriers, or both, followed by, if necessary, molding the product.

Compositions according to the invention can be prepared in any of many possible dosage forms, such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories and enemas. Compositions according to the invention can also be prepared in the form of suspensions in water, in an anhydrous medium or in a mixed medium. Aqueous suspensions may also contain substances that increase the viscosity of the suspension, including, for example, sodium-containing carboxymethyl cellulose, sorbitol and / or dextran. Such a suspension may also contain stabilizers.

In one embodiment of the invention, the pharmaceutical compositions can be prepared and used in the form of a foam. Pharmaceutical formulations in the form of foams may include, but are not limited to, formulations such as emulsions, microemulsions, creams, jellies and liposomes. Although these compositions are generally similar in nature, they may differ in their components and in the composition of the final product. Methods for preparing such compositions and preparations are essentially known to those skilled in the art of pharmacy and can be used to prepare compositions of the invention.

Emulsions

Compositions according to the invention can be obtained and prepared in the form of emulsions. Emulsions are usually heterogeneous systems consisting of one liquid dispersed in another liquid in the form of droplets, the diameter of which usually does not exceed 0.1 μm (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, Volume 1, p. 245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 2, p. 335; Higuchi et al., in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems containing two immiscible liquid phases uniformly mixed and dispersed in one another. In general terms, emulsions can be either water-in-oil (w / m) or oil-in-water (m / in) emulsions. If the aqueous phase is finely dispersed and dispersed in the form of small droplets in the bulk oil phase, then this composition is called an emulsion of the type “water in oil” (v / m). Alternatively, if the oil phase is finely divided and dispersed in the form of small droplets in a bulk aqueous phase, then such a composition is called an oil-in-water emulsion (m / v). In addition to the dispersed phases, emulsions may contain additional components and an active drug, which may be present as a solution in the aqueous phase, the oil phase, or as a separate phase. If necessary, pharmaceutical excipients such as emulsifiers, stabilizers, colorants and antioxidants can also be added to the emulsion. Pharmaceutical emulsions can also be various emulsions consisting of more than two phases, for example, in the case of emulsions of the oil-in-water-in-oil type (m / v / m) and the type water-in-oil-in-water emulsions ( in / m / in). In most cases, such complex preparations have certain advantages that simple binary emulsions do not have. Many emulsions in which individual oil droplets of an m / v type emulsion are enclosed in small water droplets constitute an i / m / v type emulsion. Similarly, a system of oil droplets included in water globules stabilized in an oil continuous phase constitutes an m / v / m emulsion.

Emulsions are characterized by low thermodynamic stability or its absence. In most cases, the dispersed or discontinuous phase of an emulsion is well dispersed in the external or continuous phase and is maintained in this form due to the emulsifiers or viscosity of the preparation. Any of the phases of this emulsion can be semi-solid or solid, as, for example, in the case of an ointment-based emulsion and creams. Another way to stabilize the emulsion is to use emulsifiers that can be included in any phase of the emulsion. In general terms, emulsifiers can be divided into four categories: synthetic surfactants, natural emulsifiers, absorption bases and finely divided solids (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 199).

Synthetic surfactants, also known as surfactants, are widely used in the manufacture of emulsion formulations and are described in the literature (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc. , New York, NY, volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, NY, 1988, volume 1, p. 199) . Surfactants are usually amphiphilic and contain a hydrophilic and hydrophobic moiety. The ratio of hydrophilicity to hydrophobicity of a surfactant is called the hydrophilic-lipophilic balance (HLB) and is a valuable tool in determining categories and in selecting surfactants for the preparation of preparations. Based on the nature of its hydrophilic group, surfactants can be divided into different classes: nonionic, anionic, cationogenic and amphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc. , New York, NY, volume 1, p. 285).

Natural emulsifiers used in emulsion preparations are lanolin, beeswax, phosphatides, lecithin and gum arabic. Absorption bases have hydrophilic properties, and therefore they can absorb water and form emulsions of the oil type, which still retain their semi-solid consistency, and such bases are anhydrous lanolin and hydrophilic petrolatum ointment. Fine emulsifiers, especially in combination with surfactants and in viscous preparations, can also be finely divided solids. Said substances are polar inorganic solids, such as heavy metal hydroxides, non-swellable clays, such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and non-polar solid substances, such as charcoal or .

A wide range of non-emulsifiable substances can also be included in emulsion formulations to impart certain properties to such emulsions. Such substances are fats, oils, waxes, fatty acids, fatty alcohols, fatty acid esters, moisturizers, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker , Inc., New York, NY, volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p . 199).

Hydrophilic colloids or hydrocolloids are natural resins and synthetic polymers such as polysaccharides (e.g., gum arabic, agar, alginic acid, carrageenan, guar gum, karaya gum and tragacanth gum), cellulose derivatives (e.g. carboxymethyl cellulose and carboxymethyl cellulose) for example, carbomers, cellulose ethers and carboxyvinyl polymers). These substances are dispersed or swell in water to form colloidal solutions that stabilize the emulsion by forming strong interfacial films around the droplets of the dispersion phase and by increasing the viscosity of the external phase.

Since emulsions often contain a number of ingredients, such as carbohydrates, proteins, styrenes and phosphatides, which can create a favorable basis for the growth of microbes, in most cases, such preparations include preservatives. Preservatives commonly used in emulsion formulations are methylparaben, propylparaben, quaternary ammonium salts, benzalkonium chloride, p-hydroxybenzoic acid esters and boric acid. Antioxidants are also usually added to emulsion formulations to prevent emulsion decomposition. The antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and synergistic antioxidants such as citric acid, tartaric acid, and lecithin.

The use of emulsion preparations by transdermal, oral and parenteral administration and methods for their preparation are described in the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1 , p. 199). Emulsion preparations for oral administration are very widely used due to their ease of preparation, as well as their effectiveness in terms of absorption and bioavailability (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc. , New York, NY, volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 199) . Mineral oil-based laxatives, oil-soluble vitamins, and high-fat nutritional products are substances that are usually administered orally in the form of m / v emulsions.

In one embodiment of the invention, the composition of dsRNA and nucleic acids is obtained in the form of microemulsions. A microemulsion can be defined as a system consisting of water, oil and an amphiphilic substance, which is an optically pure isotropic and thermodynamically stable liquid solution (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 245). Typically, microemulsions are systems that are first prepared by dispersing the oil in an aqueous solution of a surfactant, followed by the addition of a sufficient amount of the fourth component, mainly a medium chain alcohol, to form a clear system. Therefore, microemulsions have also been described as thermodynamically stable isotropically pure dispersions of two immiscible liquids that are stabilized by interfacial films composed of surfactant molecules (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed. 1989, VCH Publishers, New York, pages 185-215). Microemulsions are usually prepared by combining 3-5 components, which are oil, water, a surfactant, a secondary surfactant and an electrolyte. The type of microemulsion, namely “water in oil” (w / m) or “oil in water” (m / v), depends on the properties of the oil and on the surfactant used, as well as on the structure and geometric packaging of polar heads and hydrocarbon tails of surfactant molecules (Schott, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 271).

Phenomenological approaches have been thoroughly investigated using phase diagrams, as a result of which comprehensive information has been obtained that allows a person skilled in the art to understand the mechanism of microemulsion formation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker , Inc., New York, NY, volume 1, p. 245; Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p . 335). Compared to standard emulsions, the advantage of microemulsions lies in their ability to solubilize water-insoluble drugs in a preparation consisting of thermodynamically stable droplets that form spontaneously.

Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, nonionic surfactants, Brij 96, polyoxyethylene oleyl esters, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), monooleate tetraglycerol (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate, D They can be used alone or in combination with secondary surfactants. A secondary surfactant, usually a short-chain alcohol such as ethanol, 1-propanol and 1-butanol, improves the fluidity at the interface by penetrating the surface-active film, followed by the formation of a disordered film as a result of the formation of an empty space between the molecules surfactant.

However, microemulsions can also be obtained without the use of secondary surfactants, and alcohol-free, self-emulsifying microemulsion systems are known to those skilled in the art. The aqueous phase can usually serve, but are not limited to, water, an aqueous solution of the drug, glycerin, PEG300, PEG400, polyglycerols, propylene glycols and derivatives of ethylene glycol. Substances such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, mono-, di- and triglycerides with a medium chain length (C ₈ -C ₁₂ ), polyoxyethylene glyceryl ethers can serve as an oil phase fatty acids, fatty alcohols, polyglycol glycerides, saturated polyglycol C ₈ -C ₁₀ glycerides, vegetable oils and silicone oil.

Microemulsions are of particular interest from the point of view of solubilization of drugs and enhance the absorption of drugs. It has been suggested that lipid-based microemulsions (both m / v and i / m) increase the bioavailability of drugs, including peptides, when administered orally (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390 ; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). The advantages of microemulsions are improved solubilization of drugs, protection of the drug from enzymatic hydrolysis, possible enhancement of drug absorption due to a change in membrane fluidity and permeability induced by surfactant, ease of preparation, ease of oral administration in the form of solid dosage forms, improved clinical efficacy and low toxicity (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). In most cases, microemulsions can form spontaneously when their components interact at ambient temperature. This may be particularly preferred in the preparation of thermolabile drugs, peptides or dsRNA. Microemulsions are also effective in the transdermal delivery of active ingredients contained in cosmetics and pharmaceuticals. It is assumed that the microemulsion compositions and preparations according to the invention contribute to an increase in the level of systemic absorption of dsRNA and nucleic acids from the gastrointestinal tract, as well as an increase in the local absorption of dsRNA and nucleic acids by the cells of the gastrointestinal tract, vagina, buccal pocket and other parts of the body, which such compositions and preparations have been introduced.

The microemulsions according to the invention may also contain additional components and additives, such as sorbitan monostearate (Grill 3), labrazole and penetration enhancers, which improve the properties of this preparation and enhance the absorption of dsRNA and nucleic acids according to the invention. The permeability enhancers used in the microemulsions according to the invention can be classified as substances that belong to one of five broad categories of compounds, such as surfactants, fatty acids, bile salts, chelating agents and non-chelating and surfactant substances substances (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each compound of this class is discussed above.

Liposomes

In addition to the microemulsions that have been investigated and used to produce drugs, there are many surfactants with an ordered structure. Such structures are monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, are of great interest in terms of the specificity and long-term effects of the drugs they deliver. As used herein, the term “liposome” means a vesicle composed of amphiphilic lipids present in a spherical bilayer or bilayers.

Liposomes are unilamellar or multilamellar vesicles that have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains a composition intended for delivery. Cationic liposomes have the advantage of being able to fuse with the cell wall. Non-cationic liposomes, although they are unable to undergo efficient fusion with the cell wall, are absorbed by macrophages in vivo .

To penetrate intact mammalian skin, the lipid vesicles must pass through a series of thin pores, each of which has a diameter of less than 50 nm, under the influence of a suitable gradient created by passing through the skin. Therefore, it is desirable to use liposomes that lend themselves to a high degree of deformation and are able to pass through thin pores.

Other advantages of liposomes are that liposomes derived from natural phospholipids are biocompatible and biodegradable; liposomes may include a wide range of water and lipid soluble drugs; and liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p . 245). Upon receipt of liposome preparations, important factors such as the surface charge of lipids, the size of the vesicles, and the aqueous volume of liposomes should be considered.

Liposomes can be used to transfer and deliver the active ingredients to their site of action. Since the liposome membrane is similar in structure to biological membranes, when liposomes are applied to the tissue, these liposomes begin to penetrate the cell membranes and as the liposome penetrates the cell and moves along the cell, the contents of the liposomes are released into the cell, in which the active substance can act.

Liposomal drugs, as a method of delivery of many drugs, are the subject of intensive research. There is growing evidence that liposomes for topical administration have several advantages over other drugs. Such advantages are the relatively low level of side effects associated with high systemic absorption of the drug being administered, the increased level of accumulation of the drug being administered in the desired target area, and the possibility of introducing a wide range of drugs, both hydrophilic and hydrophobic, into the skin.

Several studies have described in detail the ability of liposomes to deliver agents, including high molecular weight DNA, to the skin. Compounds were introduced into the skin, including analgesics, antibodies, hormones, and high molecular weight DNA. In most cases, such liposomes are intended for delivery to the upper epidermis.

Liposomes are divided into two broad classes. Cationic liposomes are positively charged liposomes that interact with negatively charged DNA molecules to form a stable complex. The “positively charged DNA / liposome” complex binds to the negatively charged cell surface and is internalized to the endosome. Due to the acidic pH in the endosome, liposomes break down and their contents are released into the cell cytoplasm (Wang et al., Biochem. Biophys. Res. Commun., 1987, 147, 980-985).

Liposomes, which are pH-sensitive or negatively charged, capture DNA, but do not form a complex with it. Since DNA and lipid have the same charge, they will repel each other and will not form a complex. However, some DNA are trapped in the inner body of these liposomes. pH-sensitive liposomes have been used to deliver DNA containing the thymidine kinase gene to monolayers of cell culture. Expression of an exogenous gene was detected in target cells (Zhou et al., Journal of Controlled Release, 1992, 19, 269-274).

The liposome composition of one of the main types contains phospholipids that are not natural phosphatidylcholines. Neutral liposome compositions, for example, can be formed from dimyristoylphosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC). Anionic liposome compositions are usually formed from dimyristoylphosphatidylglycerol, and anionic fusogenic liposomes are formed mainly from dioleoylphosphatidylethanolamine (DOPE). Another type of liposome composition is obtained from phosphatidylcholine (RS), such as, for example, soybean RS and egg RS. Another type of liposome composition is prepared from mixtures of phospholipid and / or phosphatidylcholine and / or cholesterol.

Several studies have been conducted on the local delivery of liposome drugs to the skin. The application of liposomes containing interferon to the skin of guinea pigs led to a decrease in the degree of skin damage by herpes, and the delivery of interferon by other means (for example, in the form of a solution or emulsion) was ineffective (Weiner et al., Journal of Drug Targeting, 1992, 2, 405 -410). In addition, additional studies demonstrated the effectiveness of interferon administered as part of a liposome preparation intended for administration of interferon using an aqueous system, and it was concluded that such a liposome preparation was more effective than a drug for administration using an aqueous system (du Plessis et al ., Antiviral Research, 1992, 18, 259-265).

Non-ionic liposome systems, and in particular systems containing a nonionic surfactant and cholesterol, were also analyzed for their ability to deliver drugs to the skin. Non-ionic liposome preparations containing Novasome.TM. I (glyceryl dilaurate / cholesterol / polyoxyethylene stearyl ether-10) and Novasome.TM. II (glyceryl distearate / cholesterol / stearyl ether of polyoxyethylene-10) were used to deliver cyclosporin A to the dermis of mouse skin. The results showed that such nonionic liposome systems effectively contribute to the deposition of cyclosporin A in various layers of the skin (Hu et al. S.T.P. Pharma. Sci, 1994, 4, 6, 466).

Liposomes are also “sterically stabilized” liposomes, and the term used here means liposomes containing one or more specialized lipids, which, when incorporated into liposomes, increase their life time in the bloodstream compared to liposomes that do not contain such specialized lipids. Examples of sterically stabilized liposomes are liposomes in which a portion of the vesicle-forming lipid molecule of liposome (A) contains one or more glycolipids, such as monosialoganglioside G _m 1, or (B) is derivatized with one or more hydrophilic polymers such as polyethylene glycol (PEG). Not limited to any particular theory, it should be noted that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the increased half-life of these sterically stabilized liposomes in the bloodstream is due to a decrease in their level of absorption by the cells of the reticuloendothelial system (RES) (Allen et al., FEBS Letters, 1987, 223, 42; Wu et al., Cancer Research, 1993, 53, 3765).

Various liposomes containing one or more glycolipids are known to those skilled in the art. In Papahadjopoulos et al. (Ann. NY Acad. Sci., 1987, 507, 64) describes the ability of monosialoganglioside G _m 1, galactocerebroside sulfate and phosphatidylinositol to increase the half-life of liposomes in the bloodstream. These data have been interpreted by Gabizon et al. (Proc. Natl. Acad. Sci. USA, 1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, Allen et al., Describe liposomes containing (1) sphingomyelin and (2) ganglioside G _m 1 or galactocerebroside sulfate ester. US Pat. No. 5,543,152 (Webb et al.) Describes liposomes containing sphingomyelin. Liposomes containing 1,2-sn-dimyristoylphosphatidylcholine are described in WO 97/13499 (Lim et al.).

Many liposomes containing lipids derivatized with one or more hydrophilic polymers and methods for their preparation are known to those skilled in the art. In a publication by Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53, 2778) describes liposomes containing a nonionic detergent, 2C _1215G , which includes a PEG molecule. In a publication by Illum et al. (FEBS Lett., 1984, 167, 79) indicates that the hydrophilic coating of polystyrene particles with polymer glycols significantly increases the half-life of liposomes in the blood. Synthetic phospholipids modified by the addition of carboxyl groups of polyalkylene glycols (e.g., PEG) are described by Sears (US Pat. Nos. 4,426,330 and 4,534,899). In a publication by Klibanov et al. (FEBS Lett., 1990, 268, 235) describes experiments that demonstrate that liposomes containing phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have a significantly longer half-life in the bloodstream. In a publication by Blume et al. (Biochimica et Biophysica Acta, 1990, 1029, 91) such observations were directed to other PEG-derivatized phospholipids, for example DSPE-PEG, formed from a combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG molecules on their outer surface are described in European Patent No. EP 0445131 B1 and WO 90/04384, Fisher. Liposome compositions containing 1-20% moles of PEG-derivatized PE and methods for their use are described by Woodle et al. (U.S. Patent Nos. 5013556 and 5356633) and Martin et al. (US patent No. 5213804 and European patent No. EP 0496813 B1). Liposomes containing a number of other lipid-polymer conjugates are described in WO 91/05545 and in US patent No. 5225212 (both Martin et al.), As well as in WO 94/20073 (Zalipsky et al.). Liposomes containing PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al.). US Pat. No. 5,540,935 (Miyazaki et al.) And US Pat. No. 5,556,948 (Tagawa et al.) Describe PEG-containing liposomes that can also be derivatized with functional molecules on their surfaces.

Specialists know a limited number of liposomes containing nucleic acids. WO 96/40062, Thierry et al., Describes methods for encapsulating high molecular weight nucleic acids into liposomes. US Pat. No. 5,264,221 to Tagawa et al. Describes protein-associated liposomes and claims that such liposomes may include dsRNA. In US patent No. 5665710, Rahman et al., Describes some methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787, Love et al., Describes liposomes containing dsRNA targeting the raf gene.

Transfersomes are another type of liposome that is highly deformable lipid aggregates that can be attractive candidates for their use as vesicles for drug delivery. Transfersomes can be described as lipid droplets, the degree of deformability of which is so high that they can easily penetrate through pores that are smaller than the droplets themselves. Transfersomes can be adapted to the environmental conditions in which they are used, for example, they undergo self-optimization (adapt to the shape of pores in the skin), self-repair, often reach their targets without fragmentation and undergo self-loading. In order to obtain transfers, phase interface activators, usually surfactants, can be added to the standard liposome composition. Transfersomes have been used to deliver serum albumin to the skin. Transferomes-mediated delivery of serum albumin has been shown to be effective with subcutaneous injection of a solution containing serum albumin.

Surfactants are widely used in drugs such as emulsions (including microemulsions) and liposomes. The most common way to classify and evaluate the properties of many surface-active substances of various types, both natural and synthetic, is to determine the hydrophilic-lipophilic balance (HLB). In determining the category of various surfactants used in the preparations, the most commonly used criterion is the nature of the hydrophilic group (also known as the “head” group) (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, NY, 1988 , p. 285).

If a molecule of a surfactant is not ionized, then such a molecule belongs to the class of nonionic surfactants. Nonionic surfactants are widely used in the pharmaceutical and cosmetic industries and are used in a wide range of pH values. Usually their HLB values range from 2 to about 18, depending on their structure. Nonionic surfactants are nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters and ethoxylated esters. Non-ionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols and ethoxylated / propoxylated block copolymers are also included in the class of such compounds. The most prominent members of the class of nonionic surfactants are polyoxyethylene surfactants.

If a surfactant molecule carries a negative charge, if it is dissolved or dispersed in water, then such a surfactant is classified as anionic. Anionic surfactants are carboxylates such as soaps, acyl lactylates, amino acid acyl amides, sulfuric acid esters such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyltaurates and sulfosuccinates. The most important members of the class of anionic surfactants are alkyl sulfates and soaps.

If a surfactant molecule carries a positive charge, if it is dissolved or dispersed in water, then such a surfactant is classified as cationic. Cationic surfactants are quaternary ammonium salts and ethoxylated amines. The most commonly used members of compounds of this class are quaternary ammonium salts.

If a surfactant molecule carries either a positive or negative charge, then such a surfactant is classified as amphoteric. Amphoteric surfactants are acrylic acid derivatives, substituted alkyl amides, N-alkyl betaines and phosphatides.

The use of surfactants for the manufacture of drugs, pharmaceuticals and emulsions is described in the literature (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).

Permeation enhancers

In one embodiment of the invention, the use of various permeation enhancers is provided in order to ensure efficient delivery of nucleic acids, and in particular dsRNA, to the skin of animals. Most drugs are present in solution in ionized and non-ionized forms. However, only lipid-soluble or lipophilic drugs easily pass through cell membranes. It was found that even non-lipophilic drugs can pass through the cell membrane, but only if such a crossed membrane is treated with a penetration enhancer. Permeability enhancers, in addition to stimulating the diffusion of non-lipophilic drugs through cell membranes, also increase the ability of lipophilic drugs to pass.

Permeability enhancers can be classified as belonging to one of five broad categories, i.e. surfactants, fatty acids, bile salts, chelating agents and compounds that do not form chelate complexes and are not surface active agents (Lee et al ., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of the aforementioned classes of permeation enhancers is described in more detail below.

Surfactants: In accordance with the present invention, surfactants (or “surfactants”) are chemical molecules that, when dissolved in an aqueous solution, reduce the surface tension of a solution or the interfacial surface tension between an aqueous solution and another liquid As a result, the level of dsRNA absorption through the mucosa increases. In addition to bile salts and fatty acids, such permeability enhancers are, for example, sodium lauryl sulfate, polyoxyethylene-9 lauryl ether and polyoxyethylene-20 cetyl ether (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92); and perfluorinated emulsions such as FC-43 (Takahashi et al., J. Pharm. Pharmacol., 1988, 40, 252).

Fatty acids: Various fatty acids and their derivatives that act as permeation enhancers are, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, 1-monocaprate glycerol, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines or their C _1-10 alkyl p, methyl, isopropyl and tert-butyl esters) and mono- and diglycerides (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al., Critical Reviews in Therapeutic Drug Carryier Systems, 1991, p. 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654).

Bile salts: The physiological role of bile acids is to facilitate the dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts and their synthetic derivatives act as permeation enhancers. Thus, the term “bile salts” includes any of the natural components of bile acids, as well as any of their synthetic derivatives. Bile salts according to the invention are, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucocholic acid (sodium glucocholate), glycocholic acid (sodium glycocholate) , glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxy cholic acid (UDCA), sodium tauro-24.25-dihydrofusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9 lauryl ether (POE) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1- 33; Yamamoto et al., J. Pharm. Exp. Ther., 1992, 263, 25; Yamashita et al., J. Pharm. Sci., 1990, 79, 579-583).

Chelating Agents: Chelating agents used in the present invention can be defined as compounds that remove metal ions from a solution by complexing with these ions, resulting in an increase in dsRNA absorption through the mucosa. Regarding the use of such agents as penetration enhancers according to the invention, it should be noted that such chelating agents have the additional advantage that they are also DNase inhibitors, since the most famous DNA nucleases require a divalent metal ion for their catalysis, and such nucleases are inhibited by said chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Chelating agents of the invention include, but are not limited to, disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g. sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-aminoacyl beta-diket (enamines) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Buur et al., J. Control Rel. , 1990, 14, 43-51).

Compounds that do not form chelate complexes and are not surfactants: The permeability enhancers used here that do not form chelate complexes and are not surfactants can be defined as compounds that have little activity as chelating agents or as surfactants , but, nevertheless, increase the level of dsRNA absorption through the mucosa of the digestive tract (Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). Such a class of permeability enhancers includes, for example, unsaturated cyclic ureas, derivatives of 1-alkyl and 1-alkenylazacycloalkanones (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory drugs, such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al., J. Pharm. Pharmacol., 1987, 39, 621-626).

Agents that increase dsRNA uptake by cells can also be added to pharmaceutical and other compositions of the invention. For example, it is known that cationogenic lipids, such as lipofectin (Junichi et al., US patent No. 5705188), cationic derivatives of glycerol and polycationic molecules such as polylysine (Lollo et al., PCT application WO 97/30731), enhance dsRNA uptake by cells.

Other agents that can be used to enhance the permeability of the introduced nucleic acids are glycols such as ethylene glycol and propylene glycol, pyrroles such as 2-pyrrole, azones and terpenes such as limonene and menton.

Carriers

The composition of some compositions according to the invention also includes carrier compounds. As used herein, the term “carrier compound” or “carrier” may mean a nucleic acid or its analog that is inert (ie, does not have biological activity per se ) but is recognized as a nucleic acid in in vivo processes that reduce the bioavailability of a nucleic acid having biological activity, for example, by cleaving a biologically active nucleic acid or stimulating its removal from the bloodstream. Co-administration of a nucleic acid and a carrier compound, usually with an excess of carrier, can result in a significant reduction in the amount of nucleic acid released to the liver, kidneys, or other non-circulatory systems, which is likely due to competition between the carrier compound and nucleic acid for binding to their common receptor. For example, the release of partially phosphorothioate dsRNA into liver tissue can be reduced by co-administration of such dsRNA with polynosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4'-isothiocyanobenzene-2,2'-disulfonic acid (Miyao et al., Antisense Res. Dev., 1995, 5, 115-121; Takakura et al., Antisense & Nucl. Acid Drug Dev., 1996, 6, 177-183.

Fillers

Unlike carrier compounds, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent, or any other pharmacologically inert carrier for delivering one or more nucleic acids to an animal. Such an excipient can be liquid or solid, and it can be selected according to the desired route of administration, so that when combined with a nucleic acid and other components of the pharmaceutical composition, it provides the desired volume, consistency, and the like. this composition. Typical pharmaceutical carriers are, but are not limited to, binders (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose and the like); fillers (for example, lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium bisphosphate, etc.); lubricants (e.g. magnesium stearate, talc, silicon dioxide, colloidal silicon dioxide, stearic acid, metal stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrating agents (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g. sodium lauryl sulfate and the like).

Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration and without any undesired interaction with nucleic acids may also be used to prepare the compositions of the invention. Suitable pharmaceutically acceptable carriers are, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin oil, hydroxymethyl cellulose, polyvinylpyrrolidone and the like.

Formulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, anhydrous solutions in standard solvents such as alcohols, or solutions of nucleic acids in liquid or solid oil bases. These solutions may also contain buffers, diluents, and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration that do not exhibit any undesired interaction with nucleic acids may also be used.

Suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin oil, hydroxymethyl cellulose, polyvinylpyrrolidone and the like.

Pharmaceutical compositions for delivery to the respiratory tract

In another aspect, the present invention relates to the delivery of mRNA agents to the respiratory tract, and in particular for the treatment of cystic fibrosis. The respiratory tract consists of the upper respiratory tract, including the mouth of the pharynx and larynx, and the lower respiratory tract, which include the trachea with its subsequent branching into the bronchi and bronchioles. The upper and lower airways are called airways. Terminal bronchioles, in turn, are divided into respiratory bronchioles, which then lead to the final respiratory zone, alveoli or deep lung. The deep lung or alveoli are the main targets for inhaled therapeutic aerosols intended for systemic delivery of mRNA agents.

Compositions for delivery to the lungs can be administered by inhalation of the dispersion by the patient, so that the composition, and preferably the mRNA agent, in the dispersion can reach the lungs, in which they can, for example, be readily absorbed directly through the alveolar region into the bloodstream. Delivery to the lungs can be effective with systemic administration and with local administration for the treatment of pulmonary diseases.

Delivery to the lungs can be achieved by a variety of methods, including the use of inhalation preparations, aerosol preparations, micellar preparations and insufflation preparations; however, administration by inhalation can be carried out orally and / or intranasally. Delivery can be carried out using liquid aerosols, aerosol inhalers and devices for dispersing dry powders. Preferred are metering valve devices. One of the advantages of using nebulizers or inhalers is that in this case the possibility of contamination is minimized, since such devices are self-contained. Dry powder dispersion devices, for example, provide drug delivery that can be easily prepared as dry powders. The mRNA composition can be stably stored as lyophilized or spray dried powders separately or in combination with suitable carrier powders. Delivery of the composition by inhalation can be carried out using a dose timer element, which may include a timer, dosimeter, time counter or time indicator, which, when installed in this device, allows you to track the dose, monitor patient compliance with the dose regimen and / or initiate starting a dose to a patient during administration of an aerosol preparation.

Examples of pharmaceutical aerosol delivery devices are metering valve inhalers (MDI), DPI insufflators, and jet inhalers. Examples of systems for delivery by inhalation, which can be easily adapted for the introduction of the mRNA agents of interest, are described, for example, in US patent No. 5756353; 5,858,784 and in PCT Applications WO98 / 31346; WO98 / 10796; WO00 / 27359; WO01 / 54664; WO02 / 060412. Other aerosol preparations that can be used to deliver mRNA agents are described in US Pat. Nos. 6,294,153; 6344194; 6071497 and in PCT applications WO02 / 066078; WO02 / 053190; WO01 / 60420; WO00 / 66206. In addition, methods for delivering mRNA agents can be developed based on methods used to deliver other oligonucleotides (e.g., an antisense oligonucleotide) by inhalation, such as the methods described in Templin et al., Antisense Nucleic Acid Drug Dev, 2000, 10 : 359-68; Sandrasagra et al., Expert Opin Biol Ther, 2001, 1: 979-83; Sandrasagra et al., Antisense Nucleic Acid Drug Dev, 2002, 12: 177-81.

Delivery of agents according to the invention may also include the introduction of so-called “prodrugs,” that is, preparations or chemical modifications of therapeutic agents that require a certain form of processing or transport in accordance with the natural mechanism; while delivery to the desired area of the body can be carried out in combination with delivery to the respiratory tract, as well as in combination with other variants of the present invention. For example, human lungs can remove or rapidly decompose hydrolytically cleaved precipitated aerosols over a period of time from several minutes to several hours. In the upper respiratory tract, the ciliary epithelium serves as an “escalator” along which particles are removed from the respiratory tract towards the oral cavity. Pavia, D., "Lung Mucociliary Clearance," in Aerosols and the Lung: Clinical and Experimental Aspects, Clarke, SW and Pavia, D., Eds., Butterworths, London, 1984. In the deep lungs, alveolar macrophages are capable of particle phagocytosis. shortly after their precipitation. Warheit et al. Microscopy Res. Tech., 26: 412-422 (1993); and Brain, J. D., "Physiology and Pathophysiology of Pulmonary Macrophages," in The Reticuloendothelial System, S. M. Reichard and J. Filkins, Eds., Plenum, New. York., Pp. 315-327, 1985.

In preferred embodiments of the invention, and in particular in cases where systemic administration of an mRNA agent is desired, aerosol mRNA agents are prepared in the form of microparticles. Microparticles having a diameter of 0.5 to 10 microns can penetrate the lungs, passing through most natural barriers. For passage through and not around the throat, the particles must have a diameter of less than 10 microns, and to prevent exhalation, the particles must have a diameter of 0.5 microns or more.

Other components

Compositions according to the invention may additionally contain other auxiliary components, usually present in pharmaceutical compositions at levels set by a specialist. So, for example, such compositions may contain additional compatible pharmaceutically active substances, such as, for example, an antipruritic, astringent, local anesthetic or anti-inflammatory agent, or they may contain additional substances that can be used in the manufacture of the compositions according to the invention in the form various physically discrete dosage forms, namely, dyes, flavors, preservatives, antioxidants, opacifiers, thickeners and stabilizers izatory. However, such substances, when added, should not unduly affect the biological activity of the components of the compositions according to the invention. These preparations can be stabilized and, if necessary, mixed with auxiliary agents, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for changing the osmotic pressure, buffers, dyes, perfumes and / or aromatic substances and the like, which are not involved in any undesirable interaction with the nucleic acid (s) of this drug.

Aqueous suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium-containing carboxymethyl cellulose, sorbitol and / or dextran. Such a suspension may also contain stabilizers.

Some embodiments of the invention relate to pharmaceutical compositions comprising (a) one or more dsRNA agents and (b) one or more other chemotherapeutic agents that do not act by the RNA interference mechanism, but by some other mechanism. Examples of such chemotherapeutic agents include, but are not limited to, daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, ezorubicin, bleomycin, mafosfamide, ifosfamide, cytosine arabinoside, bis-chloro-aminitinositol, bis-chloro-aminitinositol, bis-chloro-aminitinositol, bis-chloro-aminitinamin, , testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexyl nitrosourea, nitrogen analogues of mustard gas, melphalan, qi lophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxycoformicin, 4-hydroxy-peroxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdrcol, methotcot, methotcot, methotcot, methotcot, methotcot, methotcot, methotcol, methotcol , vincristine, vinblastine, etoposide (VP-16), trimerexate, irinotecan, topotecan, gemcitabine, teniposide, cisplatin and diethylstilbestrol (DES). In general, see The Merck Manual of Diagnosis and Therapy, 15th Ed. 1987, pp. 1206-1228, Berkow et al., Eds., Rahway, NJ. When using the compounds of the invention in combination with chemotherapeutic agents, such chemotherapeutic agents can be used separately (e.g., 5-FU and an oligonucleotide), sequentially (e.g., 5-FU and an oligonucleotide can be administered over a period of time, and then MTX and an oligonucleotide ) or in combination with one or more other chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide or 5-FU, radiation therapy and oligonucleotide). In the compositions of the invention, the compounds of the invention can also be used in combination with anti-inflammatory drugs, including, but not limited to, non-steroidal anti-inflammatory drugs, corticosteroids, and antiviral drugs, including, but not limited to, ribivirin, vidarabine, acyclovir and ganciclovir . In general terms, see The Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al., Eds., 1987, Rahway, NJ., Pages 2499-2506 and 46-49, respectively. Other chemotherapeutic agents not containing dsRNA are also within the scope of the present invention. Two or more shared compounds may be administered together or sequentially.

The toxicity and therapeutic efficacy of such compounds can be determined using standard pharmaceutical procedures using cell cultures or experimental animals, for example, to determine LD50 (average lethal dose at which 50% of individuals die) and ED50 (average effective dose inducing therapeutic effect in 50 % of individuals). The ratio of the dose that has a toxic effect to the dose that has a therapeutic effect is called the therapeutic index and can be expressed as the ratio of LD50 / ED50. Preferred are compounds that have high therapeutic indices.

Data obtained from cell culture assays or in animal studies can be used to prepare a range of drugs for administration to humans. Doses of the compositions according to the invention are usually in the range of values which, according to calculations, give the desired concentration in the bloodstream, including ED50, and have a slight level of toxicity or no toxicity at all. These doses may vary within the indicated limits depending on the dosage form used and the route of administration. For any compound used in the method according to the invention, the therapeutically effective dose can be pre-evaluated using cell culture assays. In animal models, the dose can be calculated so that the concentration of the compound or, if necessary, the polypeptide product of the target sequence in the plasma reaches a certain concentration (for example, to achieve a reduced concentration of the polypeptide), for example, IC50 (that is, the concentration of the test compound that provides half-maximum suppression of symptoms), as can be determined in the analysis of cell culture. Such information can be used to more accurately determine the doses suitable for administration to humans. Plasma levels can be measured, for example, using high performance liquid chromatography.

The dsRNA according to the invention, in addition to their administration separately or simultaneously, as discussed above, can be introduced in combination with other known agents that are effective in treating an infection caused by an influenza virus. In any case, the practitioner can adjust the amount and time of dsRNA administration based on the results obtained using standard performance criteria known to specialists or described in this application.

Treatment Methods and Delivery Methods

A composition comprising an mRNA agent, for example, an mRNA agent targeting the influenza virus, can be administered to an individual in various ways in order to deliver it locally to the desired site of exposure or systemic delivery to the individual. Representative routes of administration include direct topical administration to the site to be treated, such as the lungs and nasal passages, as well as intravenous, intranasal, oral and ophthalmic administration. A preferred method for administering the mRNA agents of the invention is direct administration into the lungs and nasal passages in the form of a liquid, aerosol, or aerosol solution.

In general terms, the mRNA agents of the invention are administered to deliver them to an individual in the area of infection. A preferred way to achieve this delivery is by local administration into the lungs or nasal passages, for example into the tissues of the respiratory tract, by inhalation or intranasal administration, or by systemic administration, for example parenteral administration.

Preparations for inhalation or parenteral administration are well known in the art. Such preparations may include sterile aqueous solutions, which may also contain buffers, diluents and other suitable additives. For intravenous administration, the total concentration of dissolved substances should be adjusted so that such a drug is isotonic.

The active compounds described herein are preferably administered to the lung (s) or nasal passages of an individual in any suitable manner. Active compounds can be delivered by administering an aerosol suspension of particles consisting of the active compound or active compounds and inhaled by this individual. The active compound can be formulated as an aerosol in various forms, such as, but not limited to, insufflators, metered-dose inhalers, or liquid / liquid suspensions. Inhaled particles may be liquid or solid. Such particles may, but not necessarily, contain other therapeutic ingredients, such as amiloride, benzamyl or phenamyl, the selected compound being contained in an amount effective to inhibit the reabsorption of water from the secretion of the mucous membrane of the respiratory tract, as described in US patent No. 4501729.

To facilitate dispersion or transport, a pharmaceutical composition of particles may, but is not necessarily, combined with a carrier. A suitable carrier, such as sugar (i.e., lactose, sucrose, trehalose, mannitol), can be mixed with the active compound or with the compounds in any suitable ratio (for example, in a ratio of 1: 1 by weight).

Particles consisting of an active compound suitable for the practice of the present invention must be of a suitable size for inhalation, that is, they must be small enough so that after inhalation they can pass through the mouth, nose and larynx and enter the bronchi and lung alveoli. In general terms, respirable particles should have a size of about 1 to 10 microns (more specifically, less than about 5 microns). Aerosol particles having a size that makes them difficult to inhale are usually deposited in the throat and swallowed, and therefore it is preferable to minimize the number of aerosol particles not suitable for inhalation. For intranasal administration, to ensure the retention of particles in the nasal cavity, their size should preferably be in the range of 10-500 μM.

Liquid pharmaceutical compositions of the active compound used for the preparation of an aerosol can be prepared by mixing the active compound with a suitable carrier, such as sterile pyrogen-free water. The hypertonic saline solutions used to carry out the present invention are preferably sterile pyrogen-free solutions containing one to fifteen percent (by weight) of a physiologically acceptable salt, and more preferably, from three to seven percent (by weight) of a physiologically acceptable salt.

Aerosols consisting of liquid particles containing the active compound can be obtained by any suitable method, for example using a pressurized spray atomizer or an ultrasonic inhaler. See, for example, US Patent No. 4,501,729. Inhalers are commercially available devices that convert solutions or suspensions of the active ingredient into therapeutic aerosol mist by accelerating the flow of compressed gas, usually air or oxygen, through a narrow opening of a venturi or by ultrasonic mixing.

Compositions suitable for use in inhalers consist of the active ingredient in a liquid carrier, wherein said active ingredient is up to 40%, and preferably less than 20% by weight of the composition. The carrier is usually water (and most preferably sterile pyrogen-free water) or a dilute aqueous alcoholic solution, preferably isotonic, but it can also be made hypertonic to body fluids by adding, for example, sodium chloride. Optional adjuvants are preservatives if the composition is not sterile, for example methyl hydroxybenzoate, antioxidants, perfumes, volatile oils, buffering agents and surfactants.

Aerosols of solid particles containing the active compound can be similarly obtained using any generator of therapeutic aerosols containing solid particles. Aerosol generators for administering to the individual therapeutic agents consisting of solid particles produce particles suitable for inhalation and create a volume of aerosol containing a predetermined dose of the therapeutic agent at a rate suitable for administration to humans. One representative type of particulate aerosol generator is an insufflator. Suitable preparations for insufflation are finely divided powders that can be delivered with an insufflator or that can penetrate the nasal cavity by inhalation. In such an insufflator, the powder (for example, in a metered dose effective for treating the diseases described herein) is contained in capsules or in cartridges, usually made of gelatin or plastic, which either break down or open in situ , and the powder enters with a stream of air supplied using such a device after inhalation or using a hand pump. The powder used in the insufflator consists either of the active ingredient alone or of the powder mixture containing the active ingredient, a suitable powder diluent such as lactose, and optionally a surfactant. The active ingredient is usually from 0.1 to 100% by weight of the drug.

A representative aerosol generator of the second type comprises an inhaler with a metering valve. Dosing valve inhalers are sealed aerosol inhalers, usually containing a preparation comprising the active ingredient in the form of a suspension or solution in a liquefied propellant. In the process of using this device, the drug is released through a valve adapted to deliver a specific volume, usually from 10 to 200 μl, with the production of a finely divided spray containing the active ingredient. Suitable propellants are certain chlorofluorocarbon compounds, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. Such a preparation may further comprise one or more cosolvents, for example ethanol, surfactants such as oleic acid or sorbitan trioleate, an antioxidant and suitable flavoring agents.

An mRNA agent may be included in pharmaceutical compositions suitable for administration. Thus, for example, compositions may include mRNA agents of one or more species and a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity and absorption delaying agents, and the like, compatible with the pharmaceutical route of administration. The use of such media and agents for the administration of pharmaceutically active substances is well known in the art. The possibility of using any standard media or agents in these compositions is also considered, with the exception of those media or agents that are incompatible with the active compound. Auxiliary active compounds may also be incorporated into these compositions.

The introduction may be carried out by the individual himself or another person, for example, a person who cares for or treats this individual. Such a person can be any natural or legal person caring for or treating this individual, such as a hospital, hospice, doctor’s office, dispensary, medical professional, such as a doctor, nurse or other medical specialist, or spouses or guardians, such as parents. Drug treatment can be carried out by administering pre-calculated doses or using an inhaler that delivers such a measured dose.

The term “therapeutically effective amount” means the amount present in the composition and necessary to achieve the desired level of drug in the individual being treated in order to produce the expected physiological response.

The term “physiologically effective amount” means the amount delivered to an individual in order to produce the desired palliative or therapeutic effect.

The term “pharmaceutically acceptable carrier” means a carrier that can enter the lungs without causing any significant undesirable toxic effects.

The term “co-administration” means the administration to an individual of two or more agents, in particular two or more mRNA agents. Such agents may be present in a single pharmaceutical composition and may be administered simultaneously, or such agents may be present in separate preparations and may be administered to an individual sequentially. If these two agents can be detected in an individual at the same time, then it is believed that these agents are administered simultaneously.

Pharmaceutical excipients that can be used as a carrier are stabilizers, such as human serum albumin (HSA); bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusting agents or buffers; salts such as sodium chloride and the like. Such carriers may be present in crystalline or amorphous form, or they may be a mixture of these two forms.

Volume agents that are particularly valuable include compatible carbohydrates, polypeptides, amino acids, or combinations thereof. Suitable carbohydrates are monosaccharides such as galactose, D-mannose, sorbose and the like; disaccharides such as lactose, trehalose and the like; cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin; and polysaccharides such as raffinose, maltodextrins, dextrans and the like; aldites, such as mannitol, xylitol, etc. Preferred carbohydrates are lactose, trehalose, raffinose, maltodextrins and mannitol. A suitable polypeptide is aspartame. Suitable amino acids are alanine and glycine, with glycine being preferred.

Suitable pH adjusting agents or buffers are organic salts derived from organic acids and bases, such as sodium citrate, sodium ascorbate and the like, with sodium citrate being preferred.

Doses

The mRNA agent can be administered in a unit dose of about less than 75 mg per kg of body weight or about less than 70, 60, 50, 40, 30, 20, 10, 5, 2, 1, 0.5, 0, 1, 0.05, 0.01, 0.005, 0.001 or 0.0005 mg per kg of body weight and less than 200 nmol (for example, about 4.4 × 10 ¹⁶ copies) per kg of body weight or less than 1500, 750, 300, 150, 75, 15, 7.5, 1.5, 0.75, 0.15, 0.075, 0.015, 0.0075, 0.0015, 0.00075, 0.00015 nmol per kg of body weight. For example, this unit dose can be administered by injection (for example, intravenously or intramuscularly, intrathecal or directly into the organ), by inhalation, or by topical administration.

Delivery of an mRNA agent directly to an organ (e.g., to the lungs) can be carried out in a dose of about 0.00001 mg to 3 mg per organ, or preferably about 0.0001-0.001 mg per organ, about 0.03-3, 0 mg per organ, about 0.1-3.0 mg per eye, or about 0.3-3.0 mg per organ.

This dose may be an amount effective to treat or prevent a disease or disorder. It can be introduced as a preventative measure or as the main or partial component of a treatment regimen.

In one embodiment of the invention, such a unit dose is administered no more than once a day, for example no more than 2, 4, 8 or 30 days later. In another embodiment of the invention, the unit dose is not administered at any particular frequency (for example, administered irregularly). For example, a unit dose may be administered once. Since the mRNA agent mediated silencing can be maintained for several days after the introduction of the mRNA agent composition, in many cases the composition can be administered no more than once a day, or in some cases only once during the entire course of therapy.

In one embodiment of the invention, the individual is administered an initial dose and one or more maintenance doses of an mRNA agent, for example a double-stranded mRNA agent or siRNA agent (for example, a precursor, i.e. a larger mRNA agent that can be processed into a siRNA agent, or DNA that encodes an mRNA agent, for example a double-stranded mRNA agent, or a siRNA agent or its precursor.The maintenance dose or doses are usually lower than the initial dose, for example, they are less than half of the original dose. the th regimen may include the introduction of an individual dose or doses in the range from 0.01 to 75 mg / kg body weight per day, for example 70, 60, 50, 40, 30, 20, 10, 5, 2, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 or 0.0005 mg per kg of body weight per day. Supportive doses are preferably administered no more than once every 5, 10 or 30 days. In addition, the treatment regimen may be extended for a certain time, depending on the nature of a particular disease, its severity and the general health of the patient. In preferred embodiments of the invention, the dose may be administered no more than once a day, for example no more than once every 24, 36, 48 or more hours, for example no more than once every 5 or 8 days. After treatment, the patient can be examined for a change in his state of health and for the weakening of the symptoms of this pathological condition. The dose of the compound can either be increased if the patient does not have a significant response to the administered dose levels, or this dose can be reduced if the patient has a weakening of the symptoms of the pathological condition or remission of the pathological condition or if undesirable side effects.

An effective dose may be administered as a single dose or as two or more doses, as desired or as the case may be. If repeated or frequent infusions are necessary, it may be desirable to implant a delivery device, such as a pump, a stent for semi-permanent administration (e.g., intravenous, intraperitoneal, intracisternal or intracapsular) or a reservoir.

After successful treatment, it may be desirable for the patient to be given maintenance therapy to prevent recurrence of a pathological condition where the compound of the invention is administered in maintenance doses ranging from 0.001 g to 100 g per kg body weight (see US Pat. No. 6,107,094).

The concentration of the composition of the mRNA agent is an amount sufficient to effectively treat or prevent a condition or disorder, or to regulate a physiological state in humans. The concentration of the amount of mRNA agent administered depends on the parameters determined for the agent and the route of administration, for example, intranasal, buccal or intrapulmonary administration. So, for example, in order to avoid irritation or burns of the nasal passages in intranasal compositions, much lower concentrations of certain ingredients should be used. For the preparation of a suitable intranasal composition, it may sometimes be desirable to dilute which is about 10-100 times less than what is required for the oral composition.

The dose required for effective treatment of an individual may depend on several factors, including, but not limited to, the severity of the disease or disorder, previous treatment, general health, and / or age of the individual and the presence of other diseases. It should also be noted that the effective dose of the mRNA agent, such as siRNA used for treatment, can be increased or decreased during the course of treatment. Dose changes can be made based on the results of diagnostic tests. So, for example, an individual can be examined after administration of the mRNA agent composition. Based on the results of such an examination, an additional amount of the mRNA agent composition may be administered.

The dose depends on the severity of the pathological condition being treated, and on its susceptibility to this treatment, while the course of treatment can last from several days to several months or until the desired effect is achieved or the pathological state is weakened. The optimal dosage regimen can be calculated based on the assessment of drug accumulation in the patient's body. The average specialist in this field can easily determine the optimal dose and choose the method of dose administration and the frequency of their repeated administration. Optimal doses may vary depending on the relative efficacy of the individual compounds and can mainly be calculated based on EC50 concentrations that have been determined to be effective in in vitro and in vivo assays in the animal models described above.

The present invention is illustrated in detail in the following examples, which, however, should not be construed as limiting the present invention.

EXAMPLES

The nucleic acid sequences are presented below in table 3, where specific abbreviations are given in accordance with standard nomenclature.

Table 3 Abbreviations of nucleotide monomers used in the representation of nucleic acid sequences. It should be noted that these monomers, if present in the oligonucleotide, are linked to each other by 5'-3'-phosphodiester bonds Abbreviation Nucleotide (s) A 2'-deoxy-adenosine-5'-phosphate, adenosine-5'-phosphate S 2'-deoxy-cytidine-5'-phosphate, cytidine-5'-phosphate G, g 2'-deoxy-guanosine-5'-phosphate, guanosine-5'-phosphate T, t 2'-deoxy-thymidine-5'-phosphate, thymidine-5'-phosphate U, u 2'-deoxy-uridine -'-phosphate, uridine-5'-phosphate N n any 2'-deoxy nucleotide / nucleotide (G, A, C or T, g, a, c or u) am 2'-O-methyladenosine-5'-phosphate cm 2'-O-methylcytidine-5'-phosphate gm 2'-O-methylguanosine-5'-phosphate tm 2'-O-methylthymidine-5'-phosphate um 2'-O-methyluridine-5'-phosphate A , C , G , T , U , a , c , g , t , u underlined: nucleoside-5'phosphorothioate x universal base ^a) capital letters represent 2'-deoxyribonucleotides (DNA), lowercase letters represent ribonucleotides (RNA)

Reagent Source

Unless a reagent source is specifically indicated, such a reagent can be obtained from any molecular biology research reagent supplier with the standard quality / purity ratio commonly used in molecular biology.

Example 1: Sequence Selection

The construction of siRNA is carried out in order to identify siRNAs targeting the mRNA of the MP, NP, PA, PB1 and PB2 proteins of the influenza virus. In the first round, in silico siRNA selection resulted in 44 sequences targeting MP; 3 sequences targeting NP; and 1 sequence targeting PB1. None of the siRNAs specific for the PA or PB2 genes of the influenza virus passed the first round of selection, which required 80% target coverage and 80% targeting efficiency (see below).

To establish the operating program for sequence analysis, we downloaded the fastA software package (Pearson, WR, & Lipman, DJ, PNAS 1988, 85: 2444) from ftp://ftp.virginia.edu/pub/ and installed on the workstation under the operating room Suse Linux® 9.3 in accordance with standard installation parameters. To run perl scripts, you need to make sure that the perl interpreter, version 5.8.6 (copyright 1987-2004, Larry Wall) along with the installed standard Suse Linux 9.3 is functional. The BioEdit sequence alignment editor (Hall, T.A., Nucl. Acids. Symp. Ser. 1999, 41:95) was downloaded from the Brown Lab Web Server on the University of North Carolina website and installed on a computer running the Microsoft Windows 2000® operating system.

The operation for in silico selection was carried out in the following order: first, the sequences of influenza A virus of interest were loaded, then they were aligned and statistical analysis was performed to obtain data on the distribution of bases at each position compared to the calculated consensus sequence. A perl script was used to identify candidates for target areas that met certain cutoff criteria. The siRNA sequences for candidates on target regions were analyzed for specificity using the fastA algorithm and the human RefSeq database. Another perl script was used to evaluate siRNA according to predicted specificity. And finally, those siRNAs that met specificity criteria were manually selected.

The influenza A virus sequences of interest available in the database as of June 24, 2005 were downloaded from the NCBI influenza virus sequence database, available on the website of the National Center for Biotechnological Information. The number of sequences per gene for the MP, NP, PB1, PB2, and PA proteins is shown in Table 4, and their corresponding registration numbers are shown in this table.

Table 4 The number of sequences of the MP, NP, PB1, PB2 and PA genes of influenza virus of various subtypes used for in silico selection of siRNA sequences Gene H1n1 H2N2 H3n2 H5n1 H7n3 H7n7 H9N2 Total MP 10 2 13 166 28 16 128 363 NP 12 3 10 169 12 6 138 350 PB1 3 2 10 163 10 7 127 322 PB2 2 one 10 164 12 9 133 331 PA 2 2 10 171 eleven 8 124 328

The ClustalW multiple alignment function (Thompson, J.D., et al., Nucleic Acids Res. 1994; 22: 4673) of the BioEdit sequence alignment editor program was used to perform global alignment of all sequences using the default parameters for each target, respectively. The final result of nucleotide calculations at this position was obtained based on information about the distribution of nucleotides at each position with respect to the calculated consensus sequence for each target.

The following cutoff criteria were used to identify candidates for target regions of 19 nucleotides in length:

Criterion 1, target coverage: at least 80% of all sequences available for the corresponding influenza A virus gene present in the candidate region.

Criterion 2, targeting efficiency: at least 80% of all sequences in which candidate regions should be identical.

Criterion 1 was established to exclude areas of the sequence of which there is little information, and criterion 2 provides targeting a large number of subtypes.

The perl script is used to screen a file of total numerical data on the positions of nucleotides in order to identify candidates for target areas with a length of 19 bases that meet the cutoff criteria, and to create a file used as input to fastA in the next stage of analysis. For the script input, the total number of sequences for each target and a value of 80 to set the percentage were entered. All candidates for siRNA sense sequences corresponding to the most frequently occurring sequences in suitable target regions were selected and stored in a fastA-formatted file. To account for possible interactions of the protruding dTdT ends of the siRNA with the target sequence, all sequences were extended at the 5'-end by adding 'AA' to give 21-dimensional starting sequences. For each candidate for the target region, an additional file was created based on information about the properties of this region: coverage area (sequences present), targeting efficiency, total inconsistency index, number of conserved sequences and number of sequences present.

For additional selection, siRNA candidates were distributed according to their predicted ability to interact with host genes (in this case, but not limited to them, humans) (according to the potential for interaction with irrelevant targets (off-target potential)). Moreover, it is suggested that siRNA with a low potential for irrelevant interaction is the most specific in vivo .

To predict the siRNA-specific potential of irrelevant interaction, the following assumptions were made that:

1) positions 2–9 (in the direction 5 ′ → 3 ′) of the chain (unique region) make a more important contribution to the potential of irrelevant interaction than the rest of the sequence (region outside the specified unique region (minor region)) (Haley, B. & Zamore, PD, Nat Struct Mol Biol. 2004, 11: 599),

2) the indicator of irrelevant interactions can be calculated for each match, based on the identity with respect to the siRNA sequence and the position of the mismatches,

3) by introducing the corresponding nucleotide modifications into the sense strand (for example, modifications in which all nucleotides containing the pyrimidine base are 2'-O-methyl-modified nucleotides) a sense strand that does not have interfering activity with respect to RNA can be obtained ; therefore, it is only necessary to consider the potential of irrelevant interactions of the antisense chain.

To identify potential irrelevant genes, 21-dimensional sequences corresponding to suitable target regions, plus the 3'-terminal tail of AA (taking into account the protruding ends of the TT), were screened for homology with known human mRNA sequences available in publicly available databases. For this purpose, fastA (version 3.4) was used to search for all 21-dimensional source sequences in the human sequence database RefSeq (downloaded from the version available at ftp://ftp.ncbi.nih.gov/refseq/, 2005-07 -25). To determine homology along the entire length of 21 measures, a fastA search was performed using parameter-values-pairs - b 30 - g 30. As a result of this search, a list of potential irrelevant targets for siRNA candidates was obtained.

To sort the resulting list of potential irrelevant targets, the fastA output files were analyzed for the identity of the host gene with the highest inconsistency score. To calculate the mismatch index for each potential irrelevant target, irrelevant properties were established for each 21-dimensional source sequence.

1. The number of identical nucleotides for the 21-dimensional sequence (identity).

2. The rate of inconsistencies in a unique area.

The inconsistency index was calculated on the assumption that 1 and 2 have the following relationship:

Identity - 0.2 × the number of inconsistencies in a unique area.

All siRNAs were sorted by their highest rating of inconsistencies (ascending). The inconsistency score of 16.8 was used as the cut-off value for siRNA selection. 42 siRNAs specific for influenza A virus matrix protein (MP); 3 siRNAs specific for influenza A virus nucleocapsid protein (NP); and 1 siRNA specific for the main polymerase protein of the influenza A virus (PB1) had an inconsistency score of this threshold value or lower.

Taking into account the relatively low number of siRNA candidates obtained after the selection procedure described above, a numerical total assessment of nucleotides in each position was again performed using cut-off criterion 1 (target coverage), set to 70%, and criterion 2 (target specificity) when previously established 80%, after which again the distribution was carried out according to the estimates of non-compliance As a result, 2 additional siRNAs specific for the mRNA of MP protein of influenza A virus were selected with a targeting efficiency of 79.9%, and a total of 48 candidate siRNAs were selected. The sequences of these 48 siRNA candidates are shown in Table 1A.

Since the selection process described above led only to a limited number of candidate agents, the selection criterion was somewhat relaxed to obtain additional candidate agents. In particular, the above criterion 1 was weakened to 50% target coverage, criterion 2, the targeting efficiency was maintained at the same level of 80%, after which the above selection process was again repeated. As a result of this procedure, additional agents AL-DP-8001 - AL-DP-8040, listed in Table 1C, were obtained.

During the implementation of this procedure, it was found that the stage of determining the indicator of non-compliance leads to a higher dropout rate of potential agents. Therefore, to obtain a larger number of candidate agents, the selection procedure was repeated again using criterion 1 with target coverage of 80%, criterion 2 with a targeting efficiency of 80%, and the determination of the rate of inconsistencies was not performed. As a result of this procedure, additional agents were listed in Table 1D. Additional candidate agents were obtained by repeating the selection procedure again using criterion 1 with target coverage of 50% and criterion 2 with a targeting efficiency of 80%, without determining the inconsistency rate.

Additional candidate mRNA agents were identified by the inclusion of universal bases. The Perl script was used for preliminary identification of candidate sequences having target coverage and 100% targeting efficiency when up to 3 universal bases per chain are included in the non-main region (corresponding to positions 2-9 of the antisense strand) of the mRNA agent per chain. Table 1F presents the agents identified in this way. In the second round, additional mRNA agents were identified that have target coverage and targeting efficiency of 80% when the universal base is turned on. These mRNA agents are presented in table 1G.

Example 2: Synthesis of siRNA

Synthesis of nucleotides containing natural bases

Single-stranded RNAs were prepared by 1 μmol solid-phase synthesis using an Expedite 8909 synthesizer (Applied Biosystems, Applera Deutschland GmbH, Darmstadt, Germany) and glass with an adjustable pore size (CPG, 500Å, Glen Research, Sterling VA) as a solid support. RNA and RNA containing 2'-O-methyl nucleotides were obtained by solid-phase synthesis using the corresponding phosphoramidites and 2'-O-methyl-phosphoramidites, respectively (Proligo Biochemie GmbH, Hamburg, Germany). These structural blocks were included in the selected sites in the sequence of the oligoribonucleotide chain using a standard nucleoside phosphoramidite method, such as the method described in the manuals “Current protocols in nucleic acid chemistry”, Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA. Phosphorothioate bonds were introduced by replacing a solution of iodine oxidizing agent with a solution of Bokage's reagent (Chruachem Ltd, Glasgow, UK) in acetonitrile (1%). Additional auxiliary reagents were obtained from Mallinckrodt Baker (Griesheim, Germany).

Deprotection and purification by crude anion oligoribonucleotides by anion exchange HPLC was carried out in accordance with established procedures. Yields and concentrations were determined by UV absorption of a solution of the corresponding RNA at a wavelength of 260 nM using a spectral photometer (DU 640B, Beckman Coulter GmbH, Unterschleißheim, Germany). Double-stranded RNA was obtained by mixing an equimolar solution of complementary chains in an annealing buffer (20 mM sodium phosphate, pH 6.8; 100 mM sodium chloride), followed by heating in a water bath at 85-90 ° C for 3 minutes and cooling to room temperature temperature for 3-4 hours. The purified RNA solution was stored at -20 ° C until use.

All oligonucleotides obtained by the synthesis method described above did not contain a phosphate group at their outermost 5'-terminal nucleotides.

Synthesis of nucleotides containing universal bases

Synthesis of phosphoramidite and 5'-O- (4,4'-dimethoxytrityl) -2'-O- (tert-butyldimethylsilyl) -1 '- (5-nitroindole) -D-riboside on glass with an adjustable pore size used as carrier

Stage A: 1-O-methyl-D-Riboside (102)

Concentrated sulfuric acid (1.88 ml) was added to a solution of D-ribose (25 g) in dry methanol (300 ml) and stirred at room temperature for 3 days. Then the reaction mixture was neutralized with 1N. sodium hydroxide solution and concentrated to obtain a crude residue. The resulting crude residue was dissolved in methanol (200 ml) and the solids were filtered. The filtrate was concentrated to give a crude residue, which was applied to a silica gel column, eluting with a dichloromethane-methanol mixture (5: 1), whereby a pure compound (23.0 g, 82%) was obtained as a syrup.

Stage B: 1-O-methyl-2,3,5-tri-O- (2,4-dichlorobenzyl) -D-riboside (103)

To a solution of 1-O-methyl-D-riboside (13.43 g, 81.83 mmol), 18-crown-6 (1.34 g) in dry THF (100 ml) was added powdered potassium hydroxide (69 g, 1 , 23 mol) and stirred at room temperature for 40-60 minutes. Then 2,4-dichlorobenzyl chloride (51 ml, 368.2 mmol) was added dropwise and the reaction mixture was stirred at the same temperature overnight. The solids were filtered off and the filtrate was concentrated to give a crude residue, which was applied to a silica gel column, eluting with hexane-ethyl acetate (4: 1), to give a pure compound (48 g, 92%) as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.46-7.34 (m, 5H, ArH), 7.24-7.16 (m, 4H, ArH), 4.99 (s, 1H , H-1), 4.71 (dd, 2H, J _gem = 12.8 Hz, OCH ₂ Ar), 4.63-4.61 (m, 4H, 2 OCH ₂ Ar), 4.38-4 36 (m, 1H), 4.19-4.16 (dd, 1H), 3.98 (d, 1H, J = 4.4 Hz), 3.75 (dd, 1H, J = 3.6 , 7 = 10.2 Hz, H-5a), 3.66 (dd, 1H, J = 3.6, J = 10.4 Hz, H-5b), 3.37 (s, 3H, OCH ₃ ) .

Stage B: 1-bromo-2,3,5-tri-O- (2,4-dichlorobenzyl) -D-ribose (104).

To a cold solution of 1-O-methyl-2,3,5-tri-O- (2,4-dichlorobenzyl) -D-riboside (3.22 g, 5.02 mmol) in dry dichloromethane (50 ml), cooled in an ice bath, HOAc-HBr (5.3 ml, 30%) was added and stirred at 0-25 ° C for 3 hours. The reaction mixture was concentrated to obtain a crude residue, which was evaporated with toluene (3 × 30 ml) and the crude residue was obtained in the form of a syrup, which was dried under high vacuum and used in the next reaction without purification and identification.

Stage D: 1- (5-nitroindole) -2,3,5-tri-O- (2,4-dichlorobenzyl) -D-riboside (105)

To a solution of 5-nitroindole (2.44 g, 15.06 mmol) in dry CH ₃ CN (30 ml) was added sodium hydride (602 mg, 15.06 mmol, 60%) and stirred at room temperature for 3-4 hours in an argon atmosphere. Then, sugar, prepared as described above and used as a donor (104), in dry CH ₃ CN (10 ml) was added, and the mixture was stirred at the same temperature in argon atmosphere overnight. The solids were filtered off and the filtrate was concentrated to give a crude residue, which was applied to a silica gel column, eluting with hexane-ethyl acetate (3: 1), to give pure compound 105 (2.16 g, 60%) as α- and β-mixture (1: 1).

Stage E, F: 5'-O- (4,4'-dimethoxytrityl) -1 '- (5-nitroindole) -D-riboside (106) and (107)

To a cold solution of 1- (5-nitroindole) -2,3,5-tri-O- (2,4-dichlorobenzyl) -D-riboside 105 (1.16 g, 1.51 mmol) in dry dichloromethane (100 ml ) at -78 ° C, BCl ₃ in dichloromethane (23 ml, 1.0M) was added and stirred at the same temperature for 2 hours under argon and at -40 ° C for 2 hours. The reaction was quenched by the addition of methanol-dichloromethane (1: 1, 50 ml) and the mixture was neutralized with a solution of ammonia-methanol. The solids were filtered off and the filtrate was concentrated to give a crude residue, which was applied to a silica gel column, eluting with a dichloromethane-methanol mixture (10: 1), whereby a pure compound (300 mg, 68%) was obtained as an α- and β-mixture (1: 1). To a solution of the compound obtained as described above (840 mg, 2.86 mmol) in dry pyridine (3-4 ml) and DMAP (90 mg) was added DMTrCl (1.06 g) and the mixture was stirred at room temperature in the atmosphere argon during the night. The reaction mixture was concentrated to give a crude residue that was applied to a silica gel column, eluting with hexane-ethyl acetate (1: 1), to give pure compound 106 (550 mg) and compound 107 (190 mg), as well as a mixture of compounds 106 and 107 (360 mg).

Compound 106: ¹ H-NMR (CDCl ₃ , 2D g-COZY and 2D NOESY, 400 MHz): δ 8.49 (d, 1H, J = 1.6 Hz), 8.35 (d, 1H), 8 03 (dd, 1H, J = 2.0, J = 9.0 Hz), 7.70-7.69 (m, 2H), 7.47-7.14 (m, 8H, ArH), 6 86-6.81 (m, 5H, ArH), 6.71 (d, 1H, J = 3.6 Hz), 6.41 (d, J = 5.2 Hz, H'-1), 4 73 (t, 1H, J = 4.8Hz, H'-2), 4.46-4.42 (m, 3H, H'-3, H'-4, H'-5), 3.79 (s, 6H, 2OCH ₃ ), 3.51 (dd, 1H, J = 3.2, J = 10.4 Hz, H'-5a), 3.26 (dd, 1H, J = 3.2, J = 10.6 Hz, H'-5b).

Compound 107: ¹ H-NMR (CDCl ₃ , 2D g-COZY and 2D NOESY, 400 MHz): δ 8.55 (d, 1H, J = 2.0 Hz), 7.98 (dd, 1H, J = 2.4, J = 9.2 Hz), 7.60 (d, 1H, J = 9.2 Hz), 7.53 (d, 1H, J = 3.2 Hz), 7.44-7, 42 (m, 2H), 7.34-7.24 (m, 7H, ArH), 6.84-6.81 (m, 4H, ArH), 6.68 (d, 1H, J = 3.2 Hz), 6.00 (d, 1H, J = 5.2 Hz, H'-1), 4.53 (t, 1H, J = 7.6 Hz), 4.46-4.44 (m, 1H), 4.23-4.20 (m, 1H), 3.80-3.76 (m, 7H, 2OCH ₃ , H'-5), 3.55 (dd, 1H, H'-5a) 3.43 (dd, 1H, H'-5b).

Stage G: 5'-O- (4,4'-dimethoxytrityl) -2'-O- (tert-butyldimethylsilyl) -1 '- (5-nitroindole) -D-riboside (108) and 5'-O- ( 4,4'-dimethoxytrityl) -3'-O- (tert-butyldimethylsilyl) -1 '- (5-nitroindole) -D-riboside (109)

To a solution of 5'-O- (4,4'-dimethoxytrityl) -1 '- (5-nitroindole) -D-riboside (106) (550 mg, 0.92 mmol), AgNO ₃ (188 mg, 1.104 mmol) and pyridine (0.74 ml, 9.2 mmol) in dry THF (9.2 ml) was added TBDMSCl (188 mg, 1.196 mmol) and stirred at room temperature under argon overnight. The solids were filtered off and the filtrate was concentrated to give a crude residue, which was applied to a silica gel column, eluting with hexane-ethyl acetate (4: 1), to give pure compound 108 (230 mg, 35%), compound 109 (150 mg, 23%) and a mixture of compounds 108 and 109 (110 mg, 17%) with a total yield of 75%.

Compound 108: ¹ H-NMR (CDCl ₃ , 2D g-COZY, 2D NOESY, 400 MHz): δ 8.56 (d, 1H, J = 2.4 Hz), 7.88 (dd, 1H, J = 2.4, J = 8.8 Hz), 7.62 (d, 1H, J = 9.2 Hz), 7.54 (d, 1H, J = 3.6 Hz), 7.46-7, 44 (m, 2H), 7.36-7.25 (m, 6H, ArH), 6.85-6.83 (d, 5H, ArH), 6.69 (d, 1H, J = 3.6 Hz), 5.94 (d, 1H, J = 7.2 Hz, H'-1), 4.69 (dd, 1H, H'-2), 4.31-4.29 (m, 2H, H'-3, H'-4), 3.80 (s, 6H, 2OCH ₃ ), 3.58 (dd, 1H, J = 2.0, J = 10.6 Hz, H'-5a), 3.40 (dd, 1H, J = 2.0, J = 10.4 Hz, H'-5b), 2.85 (d, 1H, J = 0.8 Hz, 3'-OH), 0, 78 (s, 9H, t-Bu), -0.016 (s, 3H, SiCH ₃ ), -0.43 (s, 3H, SiCH ₃ ).

Compound 109: ¹ H-NMR (CDCl ₃ , 2D g-COZY, 2D NOESY, 400 MHz): δ 8.61 (d, 1H, J = 2.4 Hz), 8.05 (dd, 1H, J = 2.0, J = 8.8 Hz), 7.69-7.65 (m, 2H), 7.47-7.45 (m, 2H, ArH), 7.36-7.27 (m, 5H, ArH), 6.86-6.83 (m, 3H, ArH), 6.71 (d, 1H, J = 3.2 Hz), 5.99 (d, 1H, J = 4.8 Hz , H'-1), 4.51 (t, 1H, J = 4.8 Hz, J = 5.6 Hz, H'-3), 4.40-4.36 (m, 1H, H'- 2), 4.17-4.15 (m, 2H, H'-4, H'-5), 3.82 (s, 3H, OCH ₃ ), 3.81 (s, 3H, OCH ₃ ), 3.63 (dd, 1H, J = 2.4, J = 11.0 Hz, H'-5a), 3.31 (dd, 1H, J = 2.8, J = 11.0 Hz, H ' -5b), 2.95 (d, 1H, J = 6.0 Hz, 2'-OH), 0.91 (s, 9H, t-Bu), 0.05 (s, 3H, SiCH ₃ ), 0.00 (s, 3H, SiCH ₃ ).

Stage H: 5'-O- (4,4'-dimethoxytrityl) -2'-O- (tert-butyldimethylsilyl) -1 '- (5'-nitroindole) -D-riboside-3'-0-cyanoethyl-N , N-diisopropylphosphoramidate (110)

2-cyanoethyl-N, N-diisopropylchlorophosphoramidite (153 mg, 0.646 mmol) was added to a solution of 5'-O- (4,4'-dimethoxytrityl) -3'-O- (tert-butyldimethylsilyl) -1- (5-nitroindole ) -D-β-riboside 108 (230 mg, 0.323 mmol), diisopropylethylamine (306 μl, 1.78 mmol) and DMAP (10 mg) in dry dichloromethane (3 ml) and stirred at room temperature for 4-6 hours in an argon atmosphere. The reaction mixture was concentrated to give a crude residue which was applied to a silica gel column, which was saturated with 2% triethylamine in hexane and eluted with hexane-ethyl acetate (2: 1), to give the pure title compound 110 (250 mg, 85%) ) as an amorphous solid.

³¹ P-NMR (CDCl ₃ , 400 MHz): δ 149.54 (s), 146.57 (s). Analysis for C ₅₀ H ₆₅ N ₄ O ₉ PSi. Calculated: 924.43, Found: 947.43 [M + Na] ⁺ .

Stage I: 2'-hydroxy- or 3'-hydroxy-5'-O- (4,4'-dimethoxytrityl) -1- (5-nitroindole) -D-riboside (111) on solid carriers

To a mixture of 2'-OTBDMS (108) or 3'-O-TBDMS 5'-O- (4,4'-dimethoxytrityl) -1- (5-nitroindole) -Z) -D-β-riboside (109) and Succinic anhydride was added in dry dichloromethane DMAP. The reaction mixture was stirred at room temperature for 6 hours under argon. Then, another portion of succinic acid anhydride and DMAP was added, and the mixture was stirred for only 16 hours. The mixture was concentrated to give a crude residue, which was dissolved in ethyl acetate (50 ml), washed with citric acid (400 mg / 20 ml) and brine, and then dried (Na ₂ SO ₄ ). The organic layer was concentrated to obtain a crude nucleoside succinate, which was directly used in the subsequent reaction without further purification.

Nucleoside succinate, DMAP, DTNP and Ph ₃ P were mixed at room temperature for 20 minutes [Nucleoside and nucleotides, 1996, 15 (4), 879-888]. Then lcaa-CPG was added and mixed at the same temperature for 45 minutes. The solids were filtered and washed with CH ₃ CN, dichloromethane and ether. The solid carriers were dried, capped in accordance with the standard procedure and washed to obtain a solid carrier.

The nitroindole-containing glass carrier thus obtained with an adjustable pore size and phosphoramidate was used in the standard oligonucleotide synthesis method described above to prepare oligonucleotides containing natural bases.

Example 3: Analysis of siRNA in vitro

The ability of mRNA agents to inhibit the replication of influenza virus was evaluated in human cell lines in vitro or in mice in vivo . The mRNA agent was introduced into the cells, for example, by transfection or electroporation to determine its effect on the cells for a certain period of time, for example 24 hours, and the levels of infectivity were determined using plaque assay or ELISA assay. In addition to such direct analyzes, we have tested the inhibition of target gene expression by RNAi agents for certain influenza virus genes recombinantly expressed in mammalian host cells.

Viruses and cell lines

Influenza virus A / PR / 8/34 (PR8), subtype H1N1, was obtained from Charles River Laboratories (ATCC # VR-1469). Strain A / WSN / 33 (WSN), subtype H1N1, can be obtained from Thomas Chambers, University of Kentucky, Lexington, KY. USA (see Castrucci, M. R., et al., J Virol. 1992, 66: 4647) or from Dr. Peter Palese, Mount Sinai School of Medicine New York City, NY, USA (see WO 04/028471). Viral strains were propagated in an allantoic sac of fertilized chicken eggs at 34 ° C for 48-72 hours (PR8) or 37 ° C for 24 hours (WSN) (Tompkins, S. M., et al. Proc. Natl. Acad. Sci. 2004, 101: 8682).

MDCK cells were taken from the American Type Culture Collection (ATCC, Rockville MD, USA; ATCC # CCL-34) and cultured in MEM medium containing 8% heat inactivated fetal bovine serum (FBS), 2 mM L-glutamine, 1 mM pyruvate sodium, 1.5 g / l sodium bicarbonate and interchangeable amino acids at 37 ° C in an atmosphere of 5% CO ₂ with a humidity of 95%.

African green monkey Vero E6 kidney epithelial cells were taken from ATCC (Rockville MD, USA, ATCC # CRL-1586) and cultured in DMEM supplemented with 4.5 g / L D-glucose, 2 mM L-glutamine, 110 mg / L sodium pyruvate, 10% fetal bovine serum (Hyclone, Cat # 30070.03) and 0.1% penicillin / streptomycin at 37 ° C in 5% CO ₂ with a humidity of 95%.

Cos-7 African green monkey kidney cells were taken from the German collection of microorganisms and cell cultures (DSMZ, Braunschweig, Germany, DSMZ # ACC 60) and cultured in Dulbecco's modified MEM medium containing 10% fetal calf serum, 2 mM L-glutamine , 1.2 μg / ml sodium bicarbonate, 100 units. penicillin / 100 μg / ml streptomycin (Biochrom AG, Berlin, Germany).

Example 3.1: Plaque assay

Cell cultivation, siRNA transfection and virus infection

One day before transfection, MDCK cells were seeded in 24-well plates at a density of 7.5 × 10 ⁴ cells per well in 0.5 ml of culture medium. On the day of transfection, MDCK cells reached 80% confluency. Before transfection, the cells were fed 0.25 ml of culture medium.

Before adding 1.5 ml (50 μl per well) of Optimem I reagent (Invitrogen) and 90 μl (3 μl per well) of Lipofectamine 2000 (Invitrogen) in an amount sufficient to transfect a 24-well plate, they were combined in a 2-ml Sarstedt tube and incubated for 10-15 minutes at room temperature. An appropriate amount of siRNA dissolved in the annealing buffer was added to the Optimem / lipofectamine 2000 reagent mixture to obtain the desired final concentration, and then mixed and incubated for another 15-25 minutes at room temperature. Thereafter, 50 μl of the siRNA / reagent complex was added dropwise to each well in accordance with the experimental protocol. Then the plates were shaken slightly for better mixing and incubated at 37 ° C at 5% CO ₂ / humidity 95% for 14 hours.

After this, the transfection medium was carefully aspirated, the cells were washed once with 0.25-0.5 ml PBS, and 100 μl of various concentrations of PR8 in MEM medium was added to each well. After incubation at 37 ° C for 1-2 hours, 0.5 ml of coating medium was added (MEM, 20 mM HEPES, 0.075% NaHCO ₃ , 2 mM glutamine, 0.6% agarose, 0.5 μg / ml TPCK-trypsin) and the plates were incubated for 48 hours at 37 ° C in an incubator at 5% CO ₂ / humidity 95%. Then the tablets were fixed and subjected to immunological staining for viral plaques, as described below.

Immunological staining and quantification of the virus

48 hours after infection, the cells were fixed in neutrally buffered 10% formalin for 45 minutes and the wells were washed with PBS. Then the wells were blocked with a buffer to increase permeability (1 × PBS, 2% FBS, 0.5% saponin, 0.1% sodium azide) for 15 minutes at room temperature and 125 μl of a solution containing 0.5 μg / ml biotinylated mouse antibodies against influenza A virus, MAB8258B (Chemicon). After incubation for 1 hour at room temperature, the wells were washed twice with PBS to remove unbound antibody, and then 125 μl of a solution of 1 μg / ml peroxidase conjugated horseradish (HRP) streptavidin (Vector Laboratories) in PBS per well was added and the plates were incubated for 45 minutes, after which they were washed three times with PBS. Then, 200 μl of TMB substrate (Vector Laboratories # SK-4400) per well was added. After incubation in the dark for 5-10 minutes at room temperature, the colorimetric reaction was stopped by the addition of distilled water, and then the water was drained and the plates were dried in air. Stained influenza plaques were counted on an inverted optical microscope at 4X magnification. Plaque-forming activity of the cells was compared with the activity of cells transfected with lipofectamine only (pseudo-treated) and calculated by the formula: [(plaque-forming activity in the treated cells) / (plaque-forming activity in the pseudo-processed cells) × 100 =% residual infectivity.

Example 3.2: ELISA analysis

MDCK or Vero cells were seeded in 96-well plates at a density of 10 ⁴ cells per well in 0.1 ml of culture medium one day before transfection. On the day of siRNA transfection, the cells reached 80% confluence. Before transfection, the cells were fed 44 μl of culture medium.

1.08 ml (9 μl per well) of Optimem I reagent (Invitrogen) and 42 μl (0.35 μl per well) of Lipofectamine 2000 (Invitrogen) in an amount sufficient to transfect one 96-well plate were combined in a 2 ml tube Sarstedt and incubated for 10-15 minutes at room temperature. An appropriate amount of siRNA dissolved in the annealing buffer was added to the Optimem / lipofectamine 2000 reagent mixture to obtain the desired final concentration, and then mixed and incubated for another 15-25 minutes at room temperature. Thereafter, 10 μl of the siRNA / reagent complex was added dropwise to each well in accordance with the experimental protocol. Then the plates were shaken slightly for better mixing and incubated at 37 ° C at 5% CO ₂ / humidity 95% for 14 hours.

After this, the cells were washed once with PBS, infected with influenza virus PR8 in 50 μl of MEM per well and incubated for 1-2 hours. The plates were then washed once with PBS and 200 μl of MEM medium with 0.25 / 0.5 μg / ml (MDCK / VERO, respectively) trypsin was added. Two days after infection, the plates were fixed in buffered 10% formalin for 15 minutes. Cells were washed with PBS, blocked with blocking buffer for 15 minutes at room temperature, and 50 μl of a solution containing 0.5 μg / ml biotinylated monoclonal antibody against influenza A virus, MAB8258B (Chemicon) per well was added. The plates were incubated at room temperature for 1 hour, washed twice with PBS and 50 μl per well of a solution containing 1 μg / ml alkaline phosphatase conjugated streptavidin (Vector Laboratories) in blocking buffer was added. After incubation for 45 minutes and 3 times washing with PBS, 100 μl of pNPP substrate solution was added. The tablets were shown in the dark at room temperature and read at 405 nm.

Example 3.3: Inhibition of recombinantly expressed target genes of influenza virus under the action of siRNA

Consensus sequences MP (SEQ ID NO: 1453), NP (SEQ ID NO: 1454), PA (SEQ ID NO: 1455), PB1 (SEQ ID NO: 1456) and PB2 (SEQ ID NO: 1457) (see table 5) were synthesized using GENEART (Regensburg, Germany) and cloned into standard GENEART vectors. MP and PA were subcloned into psiCheck-2 vector (Promega, Mannheim, Germany) via AsiSI and NotI sites (both from NEBn, Frankfurt, Germany), and NP (PB1) and PB2 through XhoI and NotI sites, in resulting in a construct in which the influenza virus gene was located between the stop codon and the RenA luciferase polyA signal. The “correctness” of the cloning was confirmed by sequence sequencing using GATC Biotech (Konstanz, Germany).

Transfection

Cos-7 cells were seeded at a density of 1.5 × 10 ⁴ cells / well on white 96-well plates with a transparent bottom (Greiner Bio-One GmbH, Frickenhausen, Germany) in 75 μl of culture medium. Immediately after seeding the cells, 50 ng of the plasmid / well was transfected with Lipofectamine 2000 (Invitrogen) as described below for siRNA, while this plasmid was diluted in Opti-MEM medium to a final volume of 12.5 μl / well, resulting in a masterbatch for all tablet.

siRNA transfection was performed in four replicates 4 hours after transfection of the plasmid. For each well, 0.5 μl of Lipofectamine 2000 (Invitrogen GmbH, Karlsruhe, Germany) was mixed with 12 μl of Opti-MEM medium (Invitrogen) and incubated for 15 minutes at room temperature. To obtain a concentration of 50 nM siRNA in 100 μl of the volume of the transfection mixture, 1 μl of 5 μM siRNA was mixed with 11.5 μl Opti-MEM per well, then combined with Lipofectamine 2000 - Opti-MEM and incubated again for 15 minutes at room temperature. During incubation, the culture medium was removed from the wells and replaced with 75 μl / well of fresh medium. The siRNA-lipofectamine 2000 complexes were completely applied to the cells (25 μl each per well) and the cells were incubated for 24 hours at 37 ° C and 5% CO ₂ in an incubator with high humidity (Heraeus GmbH, Hanau, Germany).

Cells were harvested by removing the culture medium and applying 150 μl of a 1: 1 mixture of medium and substrate for the Dual-Glo luciferase taken from the Dual-Glo luciferase assay kits (Promega, Mannheim, Germany). Luciferase analysis was performed using Dual-Glo luciferase assay kits according to the manufacturer's instructions and the luminescence intensity was measured on a Victor-Light 1420 luminescent counter (Perkin Elmer, Rodgau-Jügesheim, Germany). The values obtained for Renilla luciferase were normalized to the values obtained for firefly luciferase. The values obtained for siRNA directed against the influenza virus gene were normalized to the value obtained for non-specific siRNA (directed against the neomycin resistance gene) and taken as 100%.

Effective siRNAs detected by screening were then characterized using dose-dependent curves. Transfections presented on dose-dependent curves were carried out at the following siRNA concentrations: 100 nM, 25 nM, 6.3 nM, 1.6 nM, 400 pM, 100 pM, 24 pM, 6 pM, 1.5 pM, 380 fM in accordance with the above protocol. IC ₅₀ values were determined by constructing a parametric curve using the XLfit program.

Table 5

Virtual consensus gene sequences of the MP proteins (SEQ ID NO: 1453), NP (SEQ ID NO: 1454), PA (SEQ ID NO: 1455), PB1 (SEQ ID NO: 1456) and PB2 (SEQ ID NO: 1457) of the virus flu for cloning into Cos-7 cells

Tables 1A, C, D, and E indicate: duplex identifier, sense and antisense strand sequences, target genes for agents, and the results of the above analyzes performed to select representative agents according to the invention. Tables 1B and H indicate: the duplex identifier, the duplex identifier of the corresponding unmodified sequence, the sequence of the sense and antisense chains, target genes for agents, namely, for selected representative agents carrying modified nucleic acid groups introduced to protect these agents from cleavage, in of which all nucleotides containing pyrimidine bases are a 2'-O-methyl group of the sense strand and all nucleotides containing pyrimidine bases in the environment and sequences 5'-ca-3 'or 5'-ua-3', contain a 2'-O-methyl group in the antisense chain, with the exception of agents in which the antisense chain does not contain nucleotides surrounded by the sequence 5'-ca-3 'or 5'-ua-3', where all the uridines surrounded by the 5'-ug-3 'sequence are 2'-O-methyl-modified nucleotides in the antisense strand (e.g. AL-DP-2295, AL-DP- 2301 and AL-DP-2302). Table 2 shows the concentrations for some particularly preferred RNAi agents, where these concentrations correspond to a 50% maximum inhibition and are calculated based on dose-response determinations in Cos-7 cells designed to express influenza genes.

Table 6

Sequences Used in Influenza A Virus Matrix Protein (MR) Assays

AY180470, the gene for the matrix protein (M) of the strain (H1N1) of the influenza virus strain A / quail / Nanhan / 12-340 / 2000, an incomplete coding sequence.

AY633213, influenza A virus matrix protein (M) gene (A / mallard / Alberta / 211/98 (H1N1)), full-length coding sequence.

AY664487, mRNA of non-functional matrix protein of influenza A virus (A / Mallard / Alberta / 119/98 (H1N1)), incomplete sequence.

M55476, matrix protein gene (M1), full-length coding sequence, M2 protein gene (M2), full-size coding sequence, type A influenza virus

M55479, matrix protein gene (M1), full-length coding sequence, M2 protein gene (M2), full-length coding sequence, type A influenza virus

M55480, matrix protein gene (M1), full-length coding sequence, M2 protein gene (M2), full-size coding sequence, type A influenza virus

M63528, genes of the M1 membrane protein and M2 membrane protein of the influenza A virus (A / turkey / Minnesota / 166/81 (H1N1)), full-length coding sequence

U49119, genes for the matrix proteins M1 and M2 (M) of influenza A virus, full-length coding sequence.

Z26859, genes for the matrix proteins M and M2 of influenza virus type A

Z26860, genes for the matrix proteins M and M2 of type A influenza virus

AY422021, influenza A virus matrix 1 (M) matrix protein gene (A / duck / Hokkaido / 95/01 (H2N2)), incomplete coding sequence.

M12699, RNA segment 7, encoding the M1 and M2 proteins of avian influenza A virus, A / Mallard / NY / 6750/78, full-length coding sequence.

AF213915, gene segment 7 gene matrix protein (M) of influenza A virus (A / chicken / Italy / 5945/95 (H3N2)), incomplete coding sequence.

AY180498, the matrix protein (M) gene of the influenza A virus strain (A / chicken / Nanhan / 3-120 / 2001 (H3N2)), an incomplete coding sequence.

AY664458, mRNA of the non-functional matrix protein of the influenza A virus (A / common stonefish / Delaware / 142/99 (H3N2)), incomplete sequence.

AY769614, influenza A virus matrix protein gene (A / turkey / Ohio / 313053/04 (H3N2)), incomplete coding sequence.

AY779257, matrix protein 2 (M) gene, incomplete coding sequence, and matrix protein 1 (M) gene, full-length coding sequence, influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)).

AY779258, matrix protein 2 (M) gene, incomplete coding sequence, and matrix protein 1 (M) gene, full-length coding sequence, influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)).

AY862623, the gene matrix protein (M) gene for influenza A virus (A / Ck / Korea / S6 / 03 (H3N2)), a full-length coding sequence.

AY862624, influenza A virus matrix protein (M) gene (A / duck / Korea / S7 / 03 (H3N2)), full-length coding sequence.

AY862625, the matrix protein (M) gene of the influenza A virus (A / Dk / Korea / S8 / 03 (H3N2)), a full-length coding sequence.

AY862626, influenza A virus matrix protein (M) gene (A / duck / Korea / S9 / 03 (H3N2)), full-length coding sequence.

AY862627, influenza A virus matrix protein (M) gene (A / duck / Korea / S10 / 03 (H3N2)), full-length coding sequence.

AY862628, influenza A virus matrix protein (M) gene (A / pigeon / Korea / S11 / 03 (H3N2)), full-length coding sequence.

Z26858, genes for the matrix proteins M and M2 of type A influenza virus

AB166865, genes for the membrane ion channel of the matrix protein M1 and M2 of influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)), full-length coding sequence.

AB188819, genes for membrane ion channel 2, matrix protein 1, M2, M1, influenza A virus (A / chicken / Oita / 8/2004 (H5N1)), full-length coding sequence.

AF509043, the M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / FY150 / 01 (H5N1)), a full-length coding sequence.

AF509044, M1 (M1) protein gene of influenza A virus (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), full-length coding sequence.

AF509045, influenza A virus M1 (M1) protein gene (A / silk chicken / Hong Kong / SF189 / 01 (H5N1)), full-length coding sequence.

AF509046, influenza A virus M1 (M1) protein gene (A / quail / Hong Kong / SF203 / 01 (H5N1)), full-length coding sequence.

AF509047, the influenza A virus M1 (M1) protein gene (A / pigeon / Hong Kong / SF215 / 01 (H5N1)), full-length coding sequence.

AF509048, influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / SF219 / 01 (H5N1)), full-length coding sequence.

AF509049, the M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / 715.5 / 01 (H5N1)), a full-length coding sequence.

AF509050, gene of the M1 (M1) protein of the influenza A virus (A / chicken / Hong Kong / 751.1 / 01 (H5N1)), full-length coding sequence.

AF509051, the influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / 822.1 / 01 (H5N1)), a full-length coding sequence.

AF509052, influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / 829.2 / 01 (H5N1)), full-length coding sequence.

AF509053, the M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / 830.2 / 01 (H5N1)), a full-length coding sequence.

AF509054, the influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / 858.3 / 01 (H5N1)), a full-length coding sequence.

AF509055, M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / 866.3 / 01 (H5N1)), full-length coding sequence.

AF509056, influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / 867.1 / 01 (H5N1)), full-length coding sequence.

AF509057, the influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / 879.1 / 01 (H5N1)), a full-length coding sequence.

AF509058, influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / 873.3 / 01 (H5N1)), full-length coding sequence.

AF509059, the M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / 876.1 / 01 (H5N1)), a full-length coding sequence.

AF509060, M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / 891.1 / 01 (H5N1)), full-length coding sequence.

AF509061, the M1 (M1) protein gene of influenza A virus (A / chicken / Hong Kong / 893.2 / 01 (H5N1)), a full-length coding sequence.

AF509062, gene for the M1 (M1) protein of the influenza A virus (A / goose / Hong Kong / 76.1 / 01 (H5N1)), a full-length coding sequence.

AF509063, M1 (M1) protein gene of influenza A virus (A / goose / Hong Kong / ww100 / 01 (H5N1)), full-length coding sequence.

AF509064, influenza A virus M1 (M1) protein gene (A / duck / Hong Kong / 573.4 / 01 (H5N1)), full-length coding sequence.

AF509065, influenza A virus M1 (M1) protein gene (A / duck / Hong Kong / 646.3 / 01 (H5N1)), full-length coding sequence.

AY059506, gene segment 7 gene matrix protein (M) virus of influenza A virus (A / goose / Hong Kong / ww26 / 2000 (H5N1)), an incomplete coding sequence.

AY059507 gene segment 7 gene matrix protein (M) virus of influenza A (A / goose / Hong Kong / ww28 / 2000 (H5N1)), an incomplete coding sequence.

AY059508, gene segment 7 gene matrix protein (M) virus of influenza A virus (A / duck / Hong Kong / ww381 / 2000 (H5N1)), an incomplete coding sequence.

AY059509, gene segment 7 gene matrix protein (M) virus of influenza A virus (A / duck / Hong Kong / ww461 / 2000 (H5N1)), an incomplete coding sequence.

AY059510, gene segment 7 gene matrix protein (M) virus of influenza A virus (A / goose / Hong Kong / ww491 / 2000 (H5N1)), an incomplete coding sequence.

AY059511, influenza A virus matrix protein (M) segment 7 gene (A / duck / Hong Kong / 2986.1 / 2000 (H5N1)), incomplete coding sequence.

AY059512, gene segment 7 gene matrix protein (M) of influenza A virus (A / goose / Hong Kong / 3014.8 / 2000 (H5N1)), incomplete coding sequence.

AY075029, the gene for matrix protein 1 and matrix protein 2 (M) of influenza A virus (A / chicken / Hong Kong / 317.5 / 2001 (H5N1)), a full-length coding sequence.

AY075035, the gene for matrix protein 1 and matrix protein 2 (M) of influenza A virus (A / duck / Hong Kong / 380.5 / 2001 (H5N1)), a full-length coding sequence.

AY221530, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / NT873.3 / 01-MB (H5N1)), full-length coding sequence.

AY221531, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / NT873.3 / 01 (H5N1)), full-length coding sequence.

AY221532, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / FY150 / 01-MB (H5N1)), full-length coding sequence.

AY221533, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), full-length coding sequence.

AY221534, influenza A virus matrix protein (M) gene (A / pheasant / Hong Kong / FY155 / 01-MB (H5N1)), full-length coding sequence.

AY221535, influenza A virus matrix protein (M) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), full-length coding sequence.

AY221536, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / YU822.2 / 01-MB (H5N1)), full-length coding sequence.

AY221537, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / YU822.2 / 01 (H5N1)), full-length coding sequence.

AY221538, influenza A virus matrix protein (M) gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), full-length coding sequence.

AY518361, the M2 gene protein of the membrane ion channel and the matrix protein M1 (M) of influenza A virus (A / duck / China / E319-2 / 03 (H5N1)), a full-length coding sequence.

AY575895, influenza A virus matrix protein (M) gene (A / Gs / HK / 739.2 / 02 (H5N1)), full-length coding sequence.

AY575896, the matrix protein gene (M) gene of influenza A virus (A / Eg / HK / 757.3 / 02 (H5N1)), an incomplete coding sequence.

AY575897, the matrix protein (M) gene of the influenza A virus (A / G.H / HK / 793.1 / 02 (H5N1)), an incomplete coding sequence.

AY575898, the matrix protein gene (M) gene of influenza A virus (A / Dk / HK / 821/02 (H5N1)), an incomplete coding sequence.

AY575899, influenza A virus matrix protein (M) gene (A / Ck / HK / 31.4 / 02 (H5N1)), full-length coding sequence.

AY575900, influenza A virus matrix protein (M) gene (A / Ck / HK / 61.9 / 02 (H5N1)), full-length coding sequence.

AY575901, influenza A virus matrix protein (M) gene (A / Ck / HK / YU777 / 02 (H5N1)), full-length coding sequence.

AY575902, influenza A virus matrix protein (M) gene (A / Ck / HK / 96.1 / 02 (H5N1)), full-length coding sequence.

AY575903, the gene matrix protein (M) gene for influenza A virus (A / Ck / HK / 409.1 / 02 (H5N1)), a full-length coding sequence.

AY575904, influenza A virus matrix protein (M) gene (A / Ph / HK / sv674.15 / 02 (H5N1)), full-length coding sequence.

AY585378, mRNA of the influenza A virus matrix protein (A / duck / Fujiyan / 01/2002 (H5N1)), full-length coding sequence.

AY585379, mRNA of the influenza A virus matrix protein (A / duck / Fujiyan / 13/2002 (H5N1)), full-length coding sequence.

AY585380, mRNA of the influenza A virus matrix protein (A / duck / Fujiyan / 17/2001 (H5N1)), full-length coding sequence.

AY585381, influenza A virus matrix protein mRNA (A / duck / Fujiyan / 19/2000 (H5N1)), full-length coding sequence.

AY585382, influenza A virus matrix protein mRNA (A / duck / Guangdong / 01/2001 (H5N1)), full-length coding sequence.

AY585383, influenza A virus matrix protein mRNA (A / duck / Guangdong / 07/2000 (H5N1)), full-length coding sequence.

AY585384, influenza A virus matrix protein mRNA (A / duck / Guangdong / 12/2000 (H5N1)), full-length coding sequence.

AY585385, mRNA of the influenza A virus matrix protein (A / duck / Guangdong / 22/2002 (H5N1)), full-length coding sequence.

AY585386, influenza A virus matrix protein mRNA (A / duck / Guangdong / 40/2000 (H5N1)), full-length coding sequence.

AY585387, mRNA of the influenza A virus matrix protein (A / duck / Guangxi / 07/1999 (H5N1)), full-length coding sequence.

AY585388, mRNA of the influenza A virus matrix protein (A / duck / Guangxi / 22/2001 (H5N1)), incomplete coding sequence.

AY585389, mRNA of the influenza A virus matrix protein (A / duck / Guangxi / 35/2001 (H5N1)), full-length coding sequence.

AY585390, mRNA of the influenza A virus matrix protein (A / duck / Guangxi / 53/2002 (H5N1)), full-length coding sequence.

AY585391, influenza A virus matrix protein mRNA (A / duck / Shanghai / 08/2001 (H5N1)), full-length coding sequence.

AY585392, influenza A virus matrix protein mRNA (A / duck / Shanghai / 13/2001 (H5N1)), full-length coding sequence.

AY585393, influenza A virus matrix protein mRNA (A / duck / Shanghai / 35/2002 (H5N1)), full-length coding sequence.

AY585394, influenza A virus matrix protein mRNA (A / duck / Shanghai / 37/2002 (H5N1)), full-length coding sequence.

AY585395, influenza A virus matrix protein mRNA (A / duck / Shanghai / 38/2001 (H5N1)), full-length coding sequence.

AY585396, mRNA of the influenza A virus matrix protein (A / duck / Zheyan / 11/2000 (H5N1)), full-length coding sequence.

AY585397, influenza A virus matrix protein mRNA (A / duck / Zheyan / 52/2000 (H5N1)), full-length coding sequence.

AY585398, influenza A virus matrix protein mRNA (A / duck / Guangxi / 50/2001 (H5N1)), full-length coding sequence.

AY590578, the gene of matrix protein M2 and matrix protein M1 (M) of influenza A virus (A / chicken / Patom Highlands / Thailand / CU-K2 / 2004 (H5N1)), an incomplete and full-length coding sequence.

AY609315, segment 7 of influenza A virus (A / chicken / Guangdong / 174/04 (H5N1)), full length sequence.

AY651374, influenza A virus membrane channel 2 (M) gene, incomplete coding sequence; and the matrix protein 1 (M) gene, the full-length coding sequence, of influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)).

AY651375, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)), a full-length coding sequence.

AY651376, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)), a full-length coding sequence.

AY651377, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)), a full-length coding sequence.

AY651378, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)), a full-length coding sequence.

AY651379, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)), a full-length coding sequence.

AY651380, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)), a full-length coding sequence.

AY651381, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)).

AY651382, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)).

AY651383, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)), a full-length coding sequence.

AY651384, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / avian / Thailand / 3.1 / 2004 (H5N1)).

AY651385, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)).

AY651386, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)).

AY651391, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)), a full-length coding sequence.

AY651392, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)), a full-length coding sequence.

AY651393, ion channel membrane protein gene 2 (M) (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)).

AY651394, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)), a full-length coding sequence.

AY651395, gene membrane protein protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)), full-length coding sequence.

AY651396, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)).

AY651397, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)).

AY651398, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)), a full-length coding sequence.

AY651399, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Gf / HK / 38/2002 (H5N1)), an incomplete coding sequence.

AY651400, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)), a full-length coding sequence.

AY651401, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)), a full-length coding sequence.

AY651402, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)), a full-length coding sequence.

AY651403, gene membrane protein protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)), full-length coding sequence.

AY651404, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)), an incomplete coding sequence.

AY651405, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)), an incomplete coding sequence.

AY651406, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)), a full-length coding sequence.

AY651407, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)), a full-length coding sequence.

AY651408, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)), an incomplete coding sequence.

AY651409, ion channel membrane protein gene 2 (M) (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)).

AY651410, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)).

AY651411, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)), a full-length coding sequence.

AY651412, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)).

AY651413, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / black-headed gull / HK / 12.1 / 2003 (H5N1)), a full-length coding sequence.

AY651414, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / gray heron / HK / 861.1 / 2002 (H5N1)).

AY651415, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / feral pigeon / HK / 862.7 / 2002 (H5N1)), a full-length coding sequence.

AY651416, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / tree sparrow / HK / 864/2002 (H5N1)).

AY651417, the gene protein of the membrane protein of ion channel 2 and matrix protein 1 (M) of influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)), an incomplete coding sequence.

AY651418, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Dk / HN / 5806/2003 (H5N1)).

AY651419, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Dk / ST / 4003/2003 (H5N1)).

AY651420, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / ST / 4231/2003 (H5N1)).

AY651421, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Dk / YN / 6255/2003 (H5N1)).

AY651422, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (ADk / YN / 6445/2003 (H5N1)).

AY651423, gene channel membrane protein ion channel 2 (M) (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ck / YN / 374/2004 (H5N1)).

AY651424, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Dk / HN / 101/2004 (H5N1)).

AY651425, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Dk / HN / 303/2004 (H5N1)).

AY651426, membrane channel protein gene of ion channel 2 (M) (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / Ph / ST / 44/2004 (H5N1)).

AY651427, ion channel 2 (M) membrane protein gene (incomplete coding sequence); and the matrix protein gene 1 (M), (full-length coding sequence) of influenza A virus (A / chicken / YN / 115/2004 (H5N1)).

AY653194, segment 7 of influenza A virus (A / chicken / Jilin / 9/2004 (H5N1)), full length sequence.

AY676045, the membrane protein (M) gene of the influenza A virus strain (A / duck / Hong Kong / 821/02 (H5N1)), a full-length coding sequence.

AY676046, the membrane protein gene (M) of the influenza A virus strain (A / egret / Hong Kong / 757.2 / 03 (H5N1)) is a full-length coding sequence.

AY676047, the membrane protein (M) gene of the influenza A virus strain (A / chicken / Korea / ES / 03 (H5N1)), a full-length coding sequence.

AY676048, the membrane protein gene (M) of the influenza A virus strain (A / duck / Korea / ESD1 / 03 (H5N1)), a full-length coding sequence.

AY684709, genes for matrix protein 2 (M2) and matrix protein 1 (M1) of influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)), full-length coding sequence.

AY737292, segment 7 of influenza A virus (A / chicken / Guangdong / 191/04 (H5N1), full length sequence.

AY737298, segment 7 of influenza A virus (A / chicken / Guangdong / 178/04 (H5N1)), full length sequence.

AY737306, segment 7 of influenza A virus (A / duck / Guangdong / 173/04 (H5N1)), full length sequence.

AY770077, genes for matrix protein 2 (M2) and matrix protein 1 (M1) of influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)), full-length coding sequence.

AY770998, influenza A virus matrix protein gene (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)), full-length coding sequence.

AY818145, influenza A virus matrix protein M1 gene (A / chicken / Vietnam / C58 / 04 (H5N1)), full-length coding sequence.

AY818146, influenza A virus matrix protein M1 gene (A / quail / Vietnam / 36/04 (H5N1)), full-length coding sequence.

AY856865, segment 7 of influenza A virus (A / duck / Shandu / 093/2004 (H5N1)), full length sequence.

DQ055851, influenza A virus matrix protein M1 gene (A / chicken / Yunan / K001 / 2004 (H5N1)), full-length coding sequence.

AB189048, the genes of the membrane protein of the ion channel M2, M1; M2 and matrix protein 1 of influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)), a full-length coding sequence.

AB189056, the genes of the membrane protein of the ion channel M2, M1; M2 and matrix protein 1 of influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)), a full-length coding sequence.

AB189064, the genes of the membrane protein of the ion channel M2, M1; M2 and matrix protein 1 of influenza A virus (A / raven / Osaka / 102/2004 (H5N1)), a full-length coding sequence.

AF046082, genes for matrix protein 2 (M2) and matrix protein 1 (M1) of influenza A virus (A / chicken / Hong Kong / 220/97 (H5N1)), full-length coding sequence.

AF098560, genes for the matrix protein M2 (M) and the matrix protein M1 (M) of influenza A virus (A / chicken / Hong Kong / 258/97 (H5N1)), an incomplete coding sequence.

AF098561, genes for the matrix protein M2 (M) and the matrix protein M1 (M) of influenza A virus (A / chicken / Hong Kong / y388 / 97 (H5N1)), an incomplete coding sequence.

AF098562, genes for the matrix protein M2 (M) and matrix protein M1 (M) of influenza A virus (A / chicken / Hong Kong / 728/97 (H5N1)), an incomplete coding sequence.

AF098563, genes for the matrix protein M2 (M) and matrix protein M1 (M) of influenza A virus (A / chicken / Hong Kong / 786/97 (H5N1)), an incomplete coding sequence.

AF098564, genes for the matrix protein M2 (M) and matrix protein M1 (M) of influenza A virus (A / chicken / Hong Kong / 915/97 (H5N1)), an incomplete coding sequence.

AF098566, genes of the matrix protein M2 (M) and matrix protein M1 (M) of influenza A virus (A / duck / Hong Kong / p46 / 97 (H5N1)), an incomplete coding sequence.

AF098567, genes of the matrix protein M2 (M) and the matrix protein M1 (M) of influenza A virus (A / duck / Hong Kong / y283 / 97 (H5N1)), an incomplete coding sequence.

AF098568, genes of the matrix protein M2 (M) and matrix protein M1 (M) of influenza A virus (A / goose / Hong Kong / w355 / 97 (H5N1)), incomplete coding sequence.

AF144306, genes for the matrix proteins M1 and M2 (M) of influenza A virus (A / goose / Guangdong / 1/96 (H5N1)), alternative splicing products, full-length coding sequence.

AF216711, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / environment / Hong Kong / 437-4 / 99 (H5N1)), full-length coding sequence.

AF216719, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / environment / Hong Kong / 437-6 / 99 (H5N1)), full-length coding sequence.

AF216727, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / environment / Hong Kong / 437-8 / 99 (H5N1)), full-length coding sequence.

AF216735, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / environment / Hong Kong / 437-10 / 99 (H5N1)), full-length coding sequence.

AF359560, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / goose / Guangdong / 3/97 (H5N1)), full-length coding sequence.

AF398429, influenza A virus matrix protein 1 (M) gene (A / goose / Hong Kong / 385.3 / 2000 (H5N1)), incomplete coding sequence.

AF398430, influenza A virus matrix protein 1 (M) gene (A / goose / Hong Kong / 385.5 / 2000 (H5N1)), incomplete coding sequence.

AF468843, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / duck / Anyang / AVL-1/2001 (H5N1)), full-length coding sequence.

AF509040, influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / FY77 / 01 (H5N1)), full-length coding sequence.

AF509041, the influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), a full-length coding sequence.

AF509042, the influenza A virus M1 (M1) protein gene (A / chicken / Hong Kong / YU563 / 01 (H5N1)), a full-length coding sequence.

AF073180, genes for matrix protein 1 (M1) and matrix protein 2 (M2) of influenza A virus (A / chicken / New Jersey / 15086-3 / 94 (H7N3NSA)), full-length coding sequence.

AF073197, genes for matrix protein 1 (M1) and matrix protein 2 (M2) of influenza A virus (A / turkey / Oregon / 71 (H7N3NSB)), full-length coding sequence.

AY664433, mRNA of the non-functional matrix protein of the influenza A virus (A / Common Rockstone / New Jersey / 65/85 (H7N3)), incomplete sequence.

AY677732, influenza A virus matrix protein 1 gene (A / chicken / British Columbia / CN7-3 / 04 (H7N3)), full-length coding sequence.

AF073198, genes for matrix protein 1 (M1) and matrix protein 2 (M2) of influenza A virus (A / turkey / Colorado / 13356/91 (H7N3NSA)), full-length coding sequence.

AF073200, genes for matrix protein 1 (M1) and matrix protein 2 (M2) of influenza A virus (A / quail / Arkansas / 16309-7 / 94 (H7N3NSA)), full-length coding sequence.

AF073201, genes for matrix protein 1 (M1) and matrix protein 2 (M2) of influenza A virus (A / turkey / Utah / 24721-10 / 95 (H7N3NSA)), full-length coding sequence.

AJ627492, membrane protein 1 gene and influenza A virus membrane protein 2 gene (A / turkey / Italy / 214845/2002 (H7N3)), genomic RNA.

AJ627497, membrane protein 1 gene and influenza A virus membrane protein 2 gene (A / turkey / Italy / 220158/2002 (H7N3)), genomic RNA.

AY241600, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / chicken / New York / 12273-11 / 99 (H7N3)), full-length coding sequence.

AY241602, the genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / chicken / NY / 14714-9 / 99 (H7N3)), a full-length coding sequence.

AY241615, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / duck / NJ / 117228-7 / 01 (H7N3)), full-length coding sequence.

AY241616, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / duck / PA / 143585/01 (H7N3)), full-length coding sequence.

AY300975, influenza A virus membrane protein (M) gene (A / blue-winged teal / TX / 2/01 (H7N3), full-length coding sequence.

AY303652, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / chicken / Chile / 176822/02 (H7N3)), full-length coding sequence.

AY303653, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / chicken / Chile / 4322/02 (H7N3)), full-length coding sequence.

AY303654, matrix protein 1 gene, full length coding sequence; and matrix protein 2 gene, incomplete coding sequence, of influenza A virus (A / chicken / Chile / 4957/02 (H7N3)).

AY303655, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / chicken / Chile / 4968/02 (H7N3)), full-length coding sequence.

AY303656, genes for matrix protein 1 and matrix protein 2 of influenza A virus (A / chicken / Chile / 4977/02 (H7N3)), full-length coding sequence.

AY303657, matrix protein 1 gene, full length coding sequence; and matrix protein 2 gene, incomplete coding sequence, of influenza A virus (A / turkey / Chile / 4418/02 (H7N3)).

AY586427, influenza A virus matrix protein gene (A / turkey / Italy / 214845/02 (H7N3)), incomplete coding sequence.

AY586428, influenza A virus matrix protein gene (A / turkey / Italy / 220158/2002 (H7N3)), incomplete coding sequence.

AY586429, influenza A virus matrix protein gene (A / Mallard / Italy / 43/01 (H7N3)), incomplete coding sequence.

AY586430, influenza A virus matrix protein gene (A / Mallard / Italy / 33/01 (H7N3)), incomplete coding sequence.

AY611525, genes for matrix protein 2 (M) and matrix protein 1 (M) of influenza A virus (A / chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

AY646079, genes for matrix protein 2 and matrix protein 1 (M) of influenza A virus (A / chicken / British Columbia / GSC_man_B / 04 (H7N3)), full-length coding sequence.

AY648288, genes for matrix protein 2 (M) and matrix protein 1 (M) of influenza A virus (A / GSC_ chicken_B / British Columbia / 04 (H7N3)), full-length coding sequence.

AY650271, genes for matrix protein 2 (M) and matrix protein 1 (M) of influenza A virus (A / GSC_ chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

AJ619676, M1 gene of the membrane protein 1 of influenza A virus (A / chicken / Germany / R28 / 03 (H7N7)), genomic RNA.

AY340086, influenza A virus matrix protein gene (A / Netherlands / 124/03 (H7N7)), incomplete coding sequence.

AY340087, influenza A virus matrix protein gene (A / Netherlands / 126/03 (H7N7)), incomplete coding sequence.

AY340088, influenza A virus matrix protein gene (A / Netherlands / 127/03 (H7N7)), incomplete coding sequence.

AY340089, influenza A virus matrix protein gene (A / Netherlands / 219/03 (H7N7)), full-length coding sequence.

AY340090, influenza A virus matrix protein gene (A / Netherlands / 33/03 (H7N7)), full-length coding sequence.

AY340091, influenza A virus matrix protein gene (A / chicken / Netherlands / 1/03 (H7N7)), full-length coding sequence.

AY664468, mRNA of the non-functional matrix protein of the influenza A virus (A / common stonefish / Delaware / 134/99 (H7N7)), incomplete sequence.

L37795, the matrix protein gene (M1) and the transmembrane protein gene (M2) of the influenza A virus (A / chicken / Brescia / 1902 (H7N7), a full-length coding sequence.

L37796, the matrix protein gene (M1) and the transmembrane gene (M2) gene of influenza A virus (A / FPV / Dobson (H7N7)), a full-length coding sequence.

L37797, the matrix protein gene (M1) and the transmembrane gene (M2) gene of influenza A virus (A / FPV / Weybridge (H7N7)), a full-length coding sequence.

M23917, influenza A virus matrix protein M1 gene (A / chicken / FPV / Weybridge (H7N7)), full-length coding sequence.

M23921, influenza A virus matrix M2 protein gene (A / chicken / FPV / Weybridge (H7N7)), full-length coding sequence.

M38299, gene (segment 7) of the matrix protein (M) of influenza A virus (A / FPV / Weybridge (H7N7)), full-length coding sequence.

M63523, genes of the membrane protein M1 and membrane protein M2 of influenza A virus (A / chicken / Victoria / 1/85 (H7N7)), full-length coding sequence.

M63526, genes of the membrane protein M1 and membrane protein M2 of influenza A virus (strain A / FPV / Dobson / 27 (H7N7)), full-length coding sequence.

AB049165, genes for the membrane protein of the ion channel M1, M2, matrix protein of the influenza A virus (A / parrot / Chiba / 1/97 (H9N2)), full-length coding sequence.

AB049166, genes of the membrane protein of the ion channel M1, M2, matrix protein of influenza A virus (A / parrot / Narita / 92A / 98 (H9N2)), full-length coding sequence.

AF222671, gene of segment 7 M1 (M1) of influenza A virus (A / silk chicken / Hong Kong / SF44 / 99 (H9N2)), an incomplete coding sequence.

AF508684, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / ostrich / South Africa / 9508103/95 (H9N2)), full-length coding sequence.

AF508685, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Pakistan / 4/99 (H9N2)), an incomplete coding sequence.

AF508686, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Pakistan / 5/99 (H9N2)), an incomplete coding sequence.

AF508687, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Germany / R45 / 98 (H9N2)), full-length coding sequence.

AF508688, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / duck / Germany / 113/95 (H9N2)), full-length coding sequence.

AF508689, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Iran / 11T / 99 (H9N2)), an incomplete coding sequence.

AF508690, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Saudi Arabia / 532/99 (H9N2)), an incomplete coding sequence.

AF508691, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / pheasant / Ireland / PV18 / 97 (H9N2)), full-length coding sequence.

AF508692, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Korea / 99029/99 (H9N2)), full-length coding sequence.

AF508693, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Beijin / 8/98 (H9N2)), full-length coding sequence.

AF508694, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Guangdong / 10/00 (H9N2)), full-length coding sequence.

AF508695, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Guangdong / 11/97 (H9N2)), full-length coding sequence.

AF508696, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Heylonyan / 10/97 (H9N2)), full-length coding sequence.

AF508697, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Hanan / 62/00 (H9N2)), full-length coding sequence.

AF508698, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Ningxia / 5/99 (H9N2)), full-length coding sequence.

AF508699, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Sihua / 5/97 (H9N2)), an incomplete coding sequence.

AF508700, gene segment 7 of the matrix protein M1 (M) of influenza A virus (A / chicken / Shandu / 6/96 (H9N2)), full-length coding sequence.

AF508701, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Shiyazhuan / 2/99 (H9N2)), an incomplete coding sequence.

AF508702, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / chicken / Shenzhen / 9/97 (H9N2)), full-length coding sequence.

AF508703, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / duck / Nanyang / 1/97 (H9N2)), full-length coding sequence.

AF508704, gene segment 7 gene matrix protein M1 (M) of influenza A virus (A / quail / Shanghai / 8/96 (H9N2)), a full-length coding sequence.

AF523482, influenza A virus matrix protein (M) gene (A / duck / Shantu / 1043/00 (H9N2)), full-length coding sequence.

AF523483, influenza A virus matrix protein (M) gene (A / duck / Shantu / 2134/00 (H9N2)), full-length coding sequence.

AF523484, influenza A virus matrix protein (M) gene (A / wild duck / Shantu / 4808/01 (H9N2)), full-length coding sequence.

AF523485, influenza A virus matrix protein (M) gene (A / duck / Shantu / 1042/00 (H9N2)), full-length coding sequence.

AF523486, influenza A virus matrix protein (M) gene (A / duck / Shantu / 2143/00 (H9N2)), full-length coding sequence.

AF523487, influenza A virus matrix protein (M) gene (A / duck / Shantu / 2144/00 (H9N2)), full-length coding sequence.

AF523488, influenza A virus matrix protein (M) gene (A / duck / Shantu / 1881/00 (H9N2)), full-length coding sequence.

AF523489, influenza A virus matrix protein (M) gene (A / duck / Shantu / 1796/00 (H9N2)), full-length coding sequence.

AF523490, influenza A virus matrix protein (M) gene (A / duck / Shantu / 2102/00 (H9N2)), full-length coding sequence.

AF523491, influenza A virus matrix protein (M) gene (A / duck / Shantu / 830/00 (H9N2)), full-length coding sequence.

AF523492, influenza A virus matrix protein (M) gene (A / duck / Shantu / 2088/01 (H9N2)), full-length coding sequence.

AF523493, influenza A virus matrix protein (M) gene (A / duck / Shantu / 1605/01 (H9N2)), full-length coding sequence.

AF523494, influenza A virus matrix protein (M) gene (A / duck / Hong Kong / 610/79 (H9N2)), full-length coding sequence.

AF523495, influenza A virus matrix protein (M) gene (A / duck / Hong Kong / 552/79 (H9N2)), full-length coding sequence.

AF523496, influenza A virus matrix protein (M) gene (A / duck / Hong Kong / 289/78 (H9N2)), full-length coding sequence.

AF523497, influenza A virus matrix protein (M) gene (A / duck / Hong Kong / 86/76 (H9N2)), full-length coding sequence.

AF523498, influenza A virus matrix protein (M) gene (A / duck / Hong Kong / 366/78 (H9N2)), incomplete coding sequence.

AF536719, non-functional matrix protein protein of influenza A virus (A / chicken / Beijin / 1/95 (H9N2)), incomplete sequence.

AF536720, non-functional matrix protein gene of influenza A virus (A / chicken / Beijin / 2/97 (H9N2)), incomplete sequence.

AF536721, non-functional matrix protein protein of influenza A virus (A / chicken / Beijin / 3/99 (H9N2)), incomplete sequence.

AF536722, non-functional matrix protein gene of influenza A virus (A / chicken / Guangdong / 97 (H9N2)), incomplete sequence.

AF536723, non-functional matrix protein protein of influenza A virus (A / chicken / Hebei / 1/96 (H9N2)), incomplete sequence.

AF536724, gene for the non-functional matrix protein of influenza A virus (A / chicken / Hebei / 2/98 (H9N2)), incomplete sequence.

AF536725, non-functional matrix protein protein of influenza A virus (A / chicken / Hebei / 3/98 (H9N2)), incomplete sequence.

AF536726, non-functional matrix protein protein of influenza A virus (A / chicken / Henan / 98 (H9N2)), incomplete sequence.

AF536727, non-functional matrix protein protein of influenza A virus (A / chicken / Liaoning / 99 (H9N2)), incomplete sequence.

AF536728, non-functional matrix protein protein of influenza A virus (A / chicken / Shandu / 98 (H9N2)), incomplete sequence.

AJ291398, matrix protein 1 (M1) gene (exon 1) and matrix protein 2 (M2) gene (exons 1 and 2) of influenza A virus (A / chicken / Pakistan / 2/99 (H9N2)), genomic RNA.

AJ427865, incomplete gene matrix protein (M) gene for influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)), genomic RNA

AY180461, matrix protein (M) gene of influenza A virus (strain A / pigeon / Nanhan / 2-0461 / 2000 (H9N2), incomplete coding sequence.

AY180462, the gene matrix protein (M) gene of influenza A virus (strain A / duck / Nanhan / 11-290 / 2000 (H9N2)), an incomplete coding sequence.

AY180463, the gene matrix protein (M) gene of influenza A virus (strain A / duck / Nanhan / 11-197 / 2000 (H9N2)), an incomplete coding sequence.

AY180464, the matrix protein gene (M) gene of influenza A virus (strain A / duck / Nanhan / 11-392 / 2000 (H9N2)), an incomplete coding sequence.

AY180477, the gene matrix protein (M) gene of influenza A virus (strain A / chicken / Nanhan / 4-361 / 2001 (H9N2)), an incomplete coding sequence.

AY180485, influenza A virus matrix protein (M) gene (strain A / pigeon / Nanhan / 11-145 / 2000 (H9N2)), incomplete coding sequence.

AY180486, the gene matrix protein (M) gene of influenza A virus (strain A / duck / Nanhan / 1-0070 / 2000 (H9N2)), an incomplete coding sequence.

AY180489, influenza A virus matrix protein (M) gene (strain A / duck / Nanhan / 10-389 / 2000 (H9N2)), incomplete coding sequence.

AY180490, influenza A virus matrix protein (M) gene (strain A / chicken / Nanhan / 1-0016 / 2000 (H9N2), incomplete coding sequence.

AY180492, the gene matrix protein (M) gene of influenza A virus (strain A / pigeon / Nanhan / 7-058 / 2000 (H9N2)), an incomplete coding sequence.

AY180495, the gene matrix protein (M) gene of influenza A virus (strain A / quail / Nanhan / 2-0460 / 2000 (H9N2)), an incomplete coding sequence.

AY180502, gene matrix protein (M) gene for influenza A virus (strain A / chicken / Nanhan / 4-010 / 2000 (H9N2)), an incomplete coding sequence.

AY180504, the gene matrix protein (M) gene of influenza A virus (strain A / quail / Nanhan / 4-040 / 2000 (H9N2)), an incomplete coding sequence.

AY180506, the matrix protein gene (M) gene of influenza A virus (strain A / chicken / Nanhan / 4-301 / 2001 (H9N2)), an incomplete coding sequence.

AY180516, influenza A virus matrix protein (M) gene (strain A / duck / Nanhan / 7-092 / 2000 (H9N2)), incomplete coding sequence.

AY180519, influenza A virus matrix protein (M) gene (strain A / wild duck / Nanhan / 2-0480 / 2000 (H9N2)), incomplete coding sequence.

AY253755, genes for the matrix protein M1 and membrane protein of the ion channel M2 of influenza A virus (A / chicken / Shanghai / F / 98 (H9N2)), full-length coding sequence.

AY496852, mRNA of the matrix protein (M1) of influenza A virus (A / chicken / Mudanjiang / 0823/2000 (H9N2)), full-length coding sequence.

AY633165, influenza A virus matrix protein (M) gene (A / Mallard / Alberta / 17/91 (H9N2)), full-length coding sequence.

AY633277, matrix protein (M) gene for influenza A virus (A / Mallard / Alberta / 321/88 (H9N2)), full-length coding sequence.

AY633293, influenza A virus matrix protein (M) gene (A / Mallard / Alberta / 11/91 (H9N2)), full-length coding sequence.

AY664464, mRNA of non-functional matrix protein (A / plover / Delaware / 276/99 (H9N2)), incomplete sequence.

AY664679, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)).

AY664680, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)).

AY664681, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)).

AY664682, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)).

AY664683, genes of the membrane protein M2 (M) and membrane protein M1 (M) of influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)), incomplete coding sequence.

AY664684, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)).

AY664685, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / Guinea fowl / Hong Kong / NT101 / 03 (H9N2)).

AY664686, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)).

AY664687, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / SF1 / 03 (H9N2)).

AY664688, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)), a full-length coding sequence.

AY664689, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)).

AY664690, M2 (M) membrane protein gene, incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)).

AY664691, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / pigeon / Hong Kong / WF53 / 03 (H9N2)).

AY664692, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)).

AY664693, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / Guinea fowl / Hong Kong / NT184 / 03 (H9N2)).

AY664694, the membrane protein gene M2 (M) and the membrane protein gene M1 (M), influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)), an incomplete coding sequence.

AY664695, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)).

AY664696, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / SSP418 / 03 (H9N2)).

AY664697, the membrane protein gene M2 (M), an incomplete coding sequence; and the membrane protein gene M1 (M), a full-length coding sequence, of influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)).

AY800234, influenza A virus matrix protein (M) gene (A / chicken / Korea / S1 / 2003 (H9N2)), full-length coding sequence.

AY862614, influenza A virus matrix protein (M) gene (A / silk chicken / Korea / S3 / 03 (H9N2)), full-length coding sequence.

AY862615, influenza A virus matrix protein (M) gene (A / chicken / Korea / S4 / 03 (H9N2)), full-length coding sequence.

AY862616, influenza A virus matrix protein (M) gene (A / chicken / Korea / S5 / 03 (H9N2)), full-length coding sequence.

AY862617, the matrix protein gene (M) gene of influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)), a full-length coding sequence.

AY862618, influenza A virus matrix protein (M) gene (A / duck / Korea / S13 / 03 (H9N2)), full-length coding sequence.

AY862619, influenza A virus matrix protein (M) gene (A / pigeon / Korea / S14 / 03 (H9N2)), incomplete coding sequence.

AY862620, influenza A virus matrix protein (M) gene (A / chicken / Korea / S15 / 03 (H9N2)), full-length coding sequence.

AY862621, influenza A virus matrix protein (M) gene (A / chicken / Korea / S16 / 03 (H9N2)), full-length coding sequence.

AY862622, influenza A virus matrix protein (M) gene (A / chicken / Korea / S18 / 03 (H9N2)), full-length coding sequence.

AF156458, genes of segment 7 of the matrix protein M1 (M1) and matrix protein M2 (M2) of influenza A virus (A / chicken / Hong Kong / G9 / 97 (H9N2)), full-length coding sequence.

AF156459, genes of segment 7 of the matrix protein M1 (M1) and matrix protein M2 (M2) of influenza A virus (A / chicken / Hong Kong / G23 / 97 (H9N2)), full-length coding sequence.

AF156460, genes of segment 7 of the matrix protein M1 (M1) and matrix protein M2 (M2) of influenza A virus (A / pigeon / Hong Kong / Y233 / 97 (H9N2)), full-length coding sequence.

AF156461, genes of segment 7 of the matrix protein M1 (M1) and matrix protein M2 (M2) of influenza A virus (A / duck / Hong Kong / Y280 / 97 (H9N2)), a full-length coding sequence.

AF156462, genes of segment 7 of the matrix protein M1 (M1) and matrix protein M2 (M2) of influenza A virus (A / duck / Hong Kong / Y439 / 97 (H9N2)), full-length coding sequence.

AF156463, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / quail / Hong Kong / G1 / 97 (H9N2)).

AF156464, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / chicken / Hong Kong / 739/94 (H9N2)).

AF156465, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), incomplete coding sequence, influenza A virus (A / quail / Hong Kong / AF157 / 92 (H9N2)), incomplete coding sequence.

AF156466, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / chicken / Beijin / 1/94 (H9N2)).

AF156467, genes for segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / chicken / Korea / 38349-p96323 / 96 (H9N2)).

AF156468, genes for segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / chicken / Korea / 25232-96006 / 96 (H9N2)).

AF156469, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / Plover / Delaware / 9/96 (H9N2)).

AF156470, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / quail / Arkansas / 29209-1 / 93 (H9N2)).

AF156471, genes of segment 7 of the matrix protein M1 (M1), full-length coding sequence; and matrix protein M2 (M2), an incomplete coding sequence, of influenza A virus (A / turkey / California / 189/66 (H9N2)).

AF203788, mRNA of matrix protein 1, full-length coding sequence; and mRNA of matrix protein 2, an incomplete coding sequence, of influenza A virus (A / chicken / Korea / MS96 / 96 (H9N2)).

AF222662, gene of segment 7 M1 (M1) of influenza A virus (A / quail / Hong Kong / A17 / 99 (H9N2)), incomplete coding sequence.

AF222663, gene of segment 7 M1 (M1) of influenza A virus (A / pigeon / Hong Kong / FY6 / 99 (H9N2)), incomplete coding sequence.

AF222664, gene of segment 7 M1 (M1) of influenza A virus (A / chicken / Hong Kong / NT16 / 99 (H9N2)), incomplete coding sequence.

AF222665, gene of segment 7 M1 (M1) of influenza A virus (A / quail / Hong Kong / SSP10 / 99 (H9N2)), incomplete coding sequence.

AF222666, gene of segment 7 M1 (M1) of influenza A virus A / pheasant / Hong Kong / SSP11 / 99 (H9N2)), an incomplete coding sequence.

AF222667, gene of segment 7 M1 (M1) of influenza A virus (A / chicken / Hong Kong / FY20 / 99 (H9N2)), incomplete coding sequence.

AF222668, gene of segment 7 M1 (M1) of influenza A virus (A / chicken / Hong Kong / KC12 / 99 (H9N2)), incomplete coding sequence.

AF222669, gene of segment 7 M1 (M1) of influenza A virus (A / quail / Hong Kong / NT28 / 99 (H9N2)), incomplete coding sequence.

AF222670, gene of segment 7 M1 (M1) of influenza A virus (A / chicken / Hong Kong / SF2 / 99 (H9N2)), incomplete coding sequence.

The sequences used in the analysis of the nucleocapsid protein (NP) of influenza A virus

AF156415, influenza A virus nucleoprotein (NP) segment 5 gene (A / turkey / California / 189/66 (H9N2)), incomplete coding sequence.

AF523423, influenza A virus nucleocapsid protein (NP) gene (A / duck / Hong Kong / 86/76 (H9N2)), full-length coding sequence.

AF523424, influenza A virus nucleocapsid protein (NP) gene (A / duck / Hong Kong / 366/78 (H9N2)), incomplete coding sequence.

AF523421, influenza A virus nucleocapsid protein (NP) gene (A / duck / Hong Kong / 289/78 (H9N2)), full-length coding sequence.

AF523422, influenza A virus nucleocapsid protein (NP) gene (A / duck / Hong Kong / 552/79 (H9N2)), incomplete coding sequence.

AY633279, influenza A virus nucleocapsid protein (NP) gene (A / Mallard / Alberta / 321/88 (H9N2)), full-length coding sequence.

AY633295, influenza A virus nucleocapsid protein (NP) gene (A / Mallard / Alberta / 11/91 (H9N2)), incomplete coding sequence.

AY633167, influenza A virus nucleocapsid protein (NP) gene (A / Mallard / Alberta / 17/91 (H9N2)), full-length coding sequence.

AF156410, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Hong Kong / AF157 / 92 (H9N2)), full-length coding sequence.

AF156414, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Arkansas / 29209-1 / 93 (H9N2)), incomplete coding sequence.

AF156408, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / 739/94 (H9N2)), full-length coding sequence.

AF156409, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Beijin / 1/94 (H9N2)), full-length coding sequence.

AF536699, influenza A virus nucleoprotein (NP) gene (A / chicken / Beijin / 1/95 (H9N2)), incomplete coding sequence.

AF508596, influenza A virus nucleoprotein (NP) segment 5 gene (A / ostrich / South Africa / 9508103/95 (H9N2)), incomplete coding sequence.

AF508600, influenza A virus nucleoprotein (NP) segment 5 gene (A / duck / Germany / 113/95 (H9N2)), incomplete coding sequence.

AB020778, influenza A virus nucleoprotein gene, full-length coding sequence.

AF508613, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Shandu / 6/96 (H9N2)), incomplete coding sequence.

AF508617, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Shanghai / 8/96 (H9N2)), incomplete coding sequence.

AF536703, influenza A virus nucleoprotein (NP) gene (A / chicken / Hebei / 1/96 (H9N2)), incomplete coding sequence.

AF156411, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Korea / 38349-96323 / 96 (H9N2)), full-length coding sequence.

AF156412, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Korea / 25232-96006 / 96 (H9N2)), incomplete coding sequence.

M63779, influenza A nucleoprotein mRNA A / FPV / Dobson / “Dutch” / 27 (H7N7), full-length coding sequence.

M63784, influenza A virus nucleoprotein mRNA / teal / Iceland / 29/80 (H7N7), full-length coding sequence.

AJ620352, NP nucleoprotein gene of influenza A virus (A / chicken / Germany / R28 / 03 (H7N7)), genomic RNA.

AY342425, influenza A virus nucleocapsid protein gene (A / Netherlands / 219/03 (H7N7)), full-length coding sequence.

AY342426, influenza A virus nucleocapsid protein gene (A / Netherlands / 033/03 (H7N7)), full-length coding sequence.

AY342427, influenza A virus nucleocapsid protein gene (A / chicken / Netherlands / 1/03 (H7N7)), full-length coding sequence.

AF156413, influenza A virus nucleoprotein (NP) segment 5 gene (A / plover / Delaware / 9/96 (H9N2)), incomplete coding sequence.

AF203787, influenza A virus nucleoprotein mRNA (A / chicken / Korea / MS96 / 96 (H9N2)), full-length coding sequence.

AF156402, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / G9 / 97 (H9N2)), full-length coding sequence.

AF156403, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / G23 / 97 (H9N2)), full-length coding sequence.

AF156404, influenza A virus nucleoprotein (NP) segment 5 gene (A / pigeon / Hong Kong / Y233 / 97 (H9N2)), incomplete coding sequence.

AF156405, influenza A virus nucleoprotein (NP) segment 5 gene (A / duck / Hong Kong / Y280 / 97 (H9N2)), incomplete coding sequence.

AF156406, influenza A virus nucleoprotein (NP) segment 5 gene (A / duck / Hong Kong / Y439 / 97 (H9N2)), full-length coding sequence.

AF156407, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Hong Kong / G1 / 97 (H9N2)), incomplete coding sequence.

AF508612, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Xihuan / 5/97 (H9N2)), incomplete coding sequence.

AF536702, influenza A virus nucleoprotein (NP) gene (A / chicken / Guangdong / 97 (H9N2)), incomplete coding sequence.

AF536700, influenza A virus nucleoprotein (NP) gene (A / chicken / Beijin / 2/97 (H9N2)), incomplete coding sequence.

AF508615, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Schenzen / 9/97 (H9N2)), incomplete coding sequence.

AF508616, influenza A virus nucleoprotein (NP) segment 5 gene (A / duck / Nanyang / 1/97 (H9N2)), incomplete coding sequence.

AB049161, influenza A virus nucleoprotein (NP) gene (A / parrot / Chiba / 1/97 (H9N2)), full-length coding sequence.

AF508603, influenza A virus nucleoprotein (NP) segment 5 gene (A / pheasant / Ireland / PV18 / 97 (H9N2)), incomplete coding sequence.

AF508607, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Guangdong / 11/97 (H9N2)), incomplete coding sequence.

AF508609, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Heylonyan / 10/97 (H9N2)), incomplete coding sequence.

AF508608, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hebei / 4/98 (H9N2)), incomplete coding sequence.

AF508605, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Beijin / 8/98 (H9N2)), incomplete coding sequence.

AF508599, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Germany / R45 / 98 (H9N2)), incomplete coding sequence.

AF536708, influenza A virus nucleoprotein (NP) gene (A / chicken / Shandu / 98 (H9N2)), incomplete coding sequence.

AY253753, influenza A virus nucleoprotein (NP) gene (A / chicken / Shanghai / F / 98 (H9N2)), full-length coding sequence.

AF536704, influenza A virus nucleoprotein (NP) gene (A / chicken / Hebei / 2/98 (H9N2)), incomplete coding sequence.

AF536705, influenza A virus nucleoprotein (NP) gene (A / chicken / Hebei / 3/98 (H9N2)), incomplete coding sequence.

AF536706, influenza A virus nucleoprotein (NP) gene (A / chicken / Henan / 98 (H9N2)), incomplete coding sequence.

AB049162, influenza A virus nucleoprotein (NP) gene (A / parrot / Narita / 92A / 98 (H9N2)), full-length coding sequence.

AF186270, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Hong Kong / NT28 / 99 (H9N2)), incomplete coding sequence.

AF186271, influenza A virus nucleoprotein (NP) segment 5 gene (A / silk chicken / Hong Kong / SF43 / 99 (H9N2)), incomplete coding sequence.

AF186272, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / SF2 / 99 (H9N2)), incomplete coding sequence.

AF222614, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Hong Kong / A17 / 99 (H9N2)), incomplete coding sequence.

AF222615, influenza A virus nucleoprotein (NP) segment 5 gene (A / pigeon / Hong Kong / FY6 / 99 (H9N2)), incomplete coding sequence.

AF222616, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / NT16 / 99 (H9N2)), incomplete coding sequence.

AF222617, influenza A virus nucleoprotein (NP) segment 5 gene (A / quail / Hong Kong / SSP10 / 99 (H9N2)), incomplete coding sequence.

AF222618, influenza A virus nucleoprotein (NP) segment 5 gene (A / pheasant / Hong Kong / SSP11 / 99 (H9N2)), incomplete coding sequence.

AF536707, influenza A virus nucleoprotein (NP) gene (A / chicken / Liaoning / 99 (H9N2)), incomplete coding sequence.

AJ291394, influenza A virus nucleoprotein NP gene A (A / chicken / Pakistan / 2/99 (H9N2)), genomic RNA.

AF536701, influenza A virus nucleoprotein (NP) gene (A / chicken / Beijin / 3/99 (H9N2)), incomplete coding sequence.

AF508611, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Ningsia / 5/99 (H9N2)), incomplete coding sequence.

AF508614, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Shiyazhuan / 2/99 (H9N2)), incomplete coding sequence.

AF508604, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Korea / 99029/99 (H9N2)), incomplete coding sequence.

AF222619, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / FY20 / 99 (H9N2)), incomplete coding sequence.

AF222620, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Hong Kong / KC12 / 99 (H9N2)), incomplete coding sequence.

AF222621, influenza A virus nucleoprotein (NP) segment 5 gene (A / silk chicken / Hong Kong / SF44 / 99 (H9N2)), incomplete coding sequence.

AF508601, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Iran / 11T / 99 (H9N2)), incomplete coding sequence.

AF508602, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Saudi Arabia / 532/99 (H9N2)), incomplete coding sequence.

AF508597, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Pakistan / 4/99 (H9N2)), incomplete coding sequence.

AF508598, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Pakistan / 5/99 (H9N2)), incomplete coding sequence.

AF508606, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Guangdong / 10/00 (H9N2)), incomplete coding sequence.

AF508610, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Henan / 62/00 (H9N2)), incomplete coding sequence.

AF523410, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 1043/00 (H9N2)), incomplete coding sequence.

AF523411, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 2134/00 (H9N2)), incomplete coding sequence.

AF523413, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 1042/00 (H9N2)), incomplete coding sequence.

AF523415, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 2102/00 (H9N2)), incomplete coding sequence.

AF523416, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 830/00 (H9N2)), incomplete coding sequence.

AF523417, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 2144/00 (H9N2)), incomplete coding sequence.

AF523419, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 2143/00 (H9N2)), incomplete coding sequence.

AF523420, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 1881/00 (H9N2)), incomplete coding sequence.

AJ427864, incomplete nucleoprotein NP gene of influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)), genomic RNA.

AY180525, influenza A virus nucleoprotein (NP) gene (A / pigeon / Nanhan / 2-0461 / 2000 (H9N2)), incomplete coding sequence.

AY180534, the nucleoprotein (NP) gene of influenza A strain A strain / duck / Nanhan / 7-092 / 2000 (H9N2), an incomplete coding sequence.

AY180537, the nucleoprotein (NP) gene of influenza A strain A strain / duck / Nanhan / 11-392 / 2000 (H9N2), an incomplete coding sequence.

AY180538, influenza A virus nucleoprotein (NP) gene (A / pigeon / Nanhan / 11-145 / 2000 (H9N2)), incomplete coding sequence.

AY180542, the nucleoprotein (NP) gene of influenza A strain A strain / duck / Nanhan / 11-197 / 2000 (H9N2), an incomplete coding sequence.

AY180544, the nucleoprotein (NP) gene of influenza A strain A strain / duck / Nanhan / 11-290 / 2000 (H9N2), an incomplete coding sequence.

AY180560, influenza A virus nucleoprotein (NP) gene (A / pigeon / Nanhan / 7-058 / 2000 (H9N2)), incomplete coding sequence.

AY180562, the nucleoprotein (NP) gene of influenza A strain A strain / chicken / Nanhan / 4-010 / 2000 (H9N2), an incomplete coding sequence.

AY180563, the nucleoprotein (NP) gene of influenza A strain A strain / quail / Nanhan / 4-040 / 2000 (H9N2), an incomplete coding sequence.

AY180564, influenza A virus nucleoprotein (NP) gene (A / wild duck / Nanhan / 2-0480 / 2000 (H9N2)), incomplete coding sequence.

AY180575, influenza A virus nucleoprotein (NP) gene (A / quail / Nanhan / 2-0460 / 2000 (H9N2)), incomplete coding sequence.

AY496851, influenza A virus nucleoprotein (NP) mRNA (A / chicken / Mudanjiang / 0823/2000 (H9N2)), full-length coding sequence.

AY180581, influenza A virus nucleoprotein (NP) gene (A / chicken / Nanhan / 1-0016 / 2000 (H9N2)), incomplete coding sequence.

AY180583, the nucleoprotein (NP) gene of influenza A strain A strain / duck / Nanhan / 10-389 / 2000 (H9N2), an incomplete coding sequence.

AY180584, the nucleoprotein (NP) gene of influenza A strain A strain / duck / Nanhan / 1-0070 / 2000 (H9N2), an incomplete coding sequence.

AY768567, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0028 / 00 (H9N2)), incomplete coding sequence.

AY768568, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0037 / 00 (H9N2)), incomplete coding sequence.

AY768569, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0057 / 00 (H9N2)), incomplete coding sequence.

AY768570, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0073 / 00 (H9N2)), incomplete coding sequence.

AY768571, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0091 / 00 (H9N2)), incomplete coding sequence.

AY768572, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0140 / 00 (H9N2)), incomplete coding sequence.

AY768573, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU0146 / 00 (H9N2)), incomplete coding sequence.

AY768574, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / SNU1035C / 00 (H9N2)), incomplete coding sequence.

AY268949, influenza A virus nucleoprotein mRNA (A / chicken / Nanhan / 4/2001 (H9N2)), full-length coding sequence.

AY180578, the nucleoprotein (NP) gene of influenza A strain A strain / chicken / Nanhan / 4-301 / 2001 (H9N2), an incomplete coding sequence.

AY180551, influenza A virus nucleoprotein (NP) gene (A / chicken / Nanhan / 4-361 / 2001 (H9N2)), incomplete coding sequence.

AF523418, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 2088/01 (H9N2)), incomplete coding sequence.

AF523414, influenza A virus nucleocapsid protein (NP) gene (A / duck / Shantu / 1605/01 (H9N2)), incomplete coding sequence.

AF523412, influenza A virus nucleocapsid protein (NP) gene (A / wild duck / Shantu / 4808/01 (H9N2)), incomplete coding sequence.

AY800236, the nucleoprotein (NP) gene (A / chicken / Korea / S1 / 2003 (H9N2)), an incomplete coding sequence.

AY862646, influenza A virus nucleocapsid protein (NP) gene (A / silk chicken / Korea / S3 / 03 (H9N2)), incomplete coding sequence.

AY862647, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S4 / 03 (H9N2)), incomplete coding sequence.

AY862648, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S5 / 03 (H9N2)), incomplete coding sequence.

AY862649, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S12 / 03 (H9N2)), incomplete coding sequence.

AY862650, influenza A virus nucleocapsid protein (NP) gene (A / duck / Korea / S13 / 03 (H9N2)), incomplete coding sequence.

AY862651, influenza A virus nucleocapsid protein (NP) gene (A / pigeon / Korea / S14 / 03 (H9N2)), incomplete coding sequence.

AY862652, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S15 / 03 (H9N2)), incomplete coding sequence.

AY862653, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S16 / 03 (H9N2)), incomplete coding sequence.

AY862654, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S18 / 03 (H9N2)), incomplete coding sequence.

AY664717, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / CSW153 / 03 (H9N2)), full-length coding sequence.

AY664718, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / AP45 / 03 (H9N2)), full-length coding sequence.

AY664719, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / BD90 / 03 (H9N2)), full-length coding sequence.

AY664720, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / CSW291 / 03 (H9N2)), full-length coding sequence.

AY664721, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / CSW304 / 03 (H9N2)), full-length coding sequence.

AY664722, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / FY23 / 03 (H9N2)), full-length coding sequence.

AY664723, influenza A virus nucleoprotein (NP) gene (A / Guinea fowl / Hong Kong / NT101 / 03 (H9N2)), full-length coding sequence.

AY664724, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / NT142 / 03 (H9N2)), full-length coding sequence.

AY664725, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / SF1 / 03 (H9N2)), full-length coding sequence.

AY664726, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / SSP101 / 03 (H9N2)), full-length coding sequence.

AY664727, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / TP38 / 03 (H9N2)), full-length coding sequence.

AY664728, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / WF126 / 03 (H9N2)), full-length coding sequence.

AY664729, influenza A virus nucleoprotein (NP) gene (A / pigeon / Hong Kong / WF53 / 03 (H9N2)), full-length coding sequence.

AY664730, influenza A virus nucleoprotein (NP) gene (A / pheasant / Hong Kong / WF54 / 03 (H9N2)), full-length coding sequence.

AY664731, influenza A virus nucleoprotein (NP) gene (A / Guinea fowl / Hong Kong / NT184 / 03 (H9N2)), full-length coding sequence.

AY664732, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / WF120 / 03 (H9N2)), full-length coding sequence.

AY664733, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / NT366 / 03 (H9N2)), incomplete coding sequence.

AY664734, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / SSP418 / 03 (H9N2)), incomplete coding sequence.

AY664735, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / YU427 / 03 (H9N2)), incomplete coding sequence.

AY788915, influenza A virus nucleoprotein (NP) gene (A / chicken / China / HSS2004 (H9N2)), full-length coding sequence.

AY586423, influenza A virus nucleoprotein gene (A / Mallard / Italy / 33/01 (H7N3)), incomplete coding sequence.

AY586424, influenza A virus nucleoprotein gene (A / Mallard / Italy / 43/01 (H7N3)), incomplete coding sequence.

AY586425, influenza A virus nucleoprotein gene (A / turkey / Italy / 220158/2002 (H7N3)), incomplete coding sequence.

AY586426, influenza A virus nucleoprotein gene (A / turkey / Italy / 214845/02 (H7N3)), incomplete coding sequence.

AJ627486, NP nucleoprotein gene of influenza A virus (A / turkey / Italy / 214845/2002 (H7N3)), genomic RNA.

AJ627495, NP nucleoprotein gene of influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)), genomic RNA.

AY303658, influenza A virus nucleoprotein NP gene A (A / chicken / Chile / 176822/02 (H7N3)), full-length coding sequence.

AY303659, influenza A virus nucleoprotein NP gene A (A / chicken / Chile / 4957/02 (H7N3)), full-length coding sequence.

AY611527, influenza A virus nucleoprotein (NP) gene (A / chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

AY646081, influenza A virus nucleoprotein (NP) gene (A / chicken / British Columbia / GSC_man_B / 04 (H7N3)), full-length coding sequence.

AY648290, influenza A virus nucleoprotein (NP) gene (A / GSC_ chicken_B / British Columbia / 04 (H7N3)), full-length coding sequence.

AY650273, influenza A virus nucleoprotein (NP) gene (A / GSC_ chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

AF144303, influenza A virus nucleocapsid protein (NP) gene (A / goose / Guangdong / 1/96 (H5N1)), full-length coding sequence.

AF046084, influenza A virus nucleoprotein gene (A / chicken / Hong Kong / 220/97 (H5N1)), full-length coding sequence.

AF057293, influenza A virus nucleoprotein mRNA (A / chicken / Hong Kong / 258/97 (H5N1)), full-length coding sequence.

AF098617, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / y388 / 97 (H5N1)), full-length coding sequence.

AF098618, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / 728/97 (H5N1)), full-length coding sequence.

AF098619, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / 786/97 (H5N1)), full-length coding sequence.

AF098620, influenza A virus nucleoprotein (NP) gene (A / chicken / Hong Kong / 915/97 (H5N1)), full-length coding sequence.

AF098621, influenza A virus nucleoprotein (NP) gene (A / duck / Hong Kong / p46 / 97 (H5N1)), full-length coding sequence.

AF098622, influenza A virus nucleoprotein (NP) gene (A / duck / Hong Kong / y283 / 97 (H5N1)), full-length coding sequence.

AF098623, influenza A virus nucleoprotein (NP) gene (A / goose / Hong Kong / w355 / 97 (H5N1)), full-length coding sequence.

AF370122, influenza A virus nucleoprotein gene (A / goose / Guangdong / 3/97 (H5N1)), full-length coding sequence.

AF216712, the influenza A virus nucleoprotein gene (A / environment / Hong Kong / 437-4 / 99 (H5N1)), a full-length coding sequence.

AF216720, influenza A virus nucleoprotein gene (A / environment / Hong Kong / 437-6 / 99 (H5N1)), full-length coding sequence.

AF216728, the influenza A virus nucleoprotein gene (A / environment / Hong Kong / 437-8 / 99 (H5N1)), a full-length coding sequence.

AF216736, influenza A virus nucleoprotein gene (A / environment / Hong Kong / 437-10 / 99 (H5N1)), full-length coding sequence.

AY585429, mRNA of the influenza A virus nucleoprotein (NP) (A / duck / Guangxi / 07/1999 (H5N1)), full-length coding sequence.

AY585439, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Caiyan / 11/2000 (H5N1)), full-length coding sequence.

AY585440, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Caiyan / 52/2000 (H5N1)), full-length coding sequence.

AY585428, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Guangdong / 40/2000 (H5N1)), full-length coding sequence.

AY585423, influenza A virus nucleoprotein (NP) mRNA (A / duck / Fujiyan / 19/2000 (H5N1)), full-length coding sequence.

AY585425, influenza A virus nucleoprotein (NP) mRNA (A / duck / Guangdong / 07/2000 (H5N1)), full-length coding sequence.

AY585426, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Guangdong / 12/2000 (H5N1)), full-length coding sequence.

AY059492, segment 5 gene of the nucleocapsid protein (NP) of influenza A virus (A / goose / Hong Kong / ww26 / 2000 (H5N1)), an incomplete coding sequence.

AY059493, gene segment 5 nucleocapsid protein (NP) of influenza A virus (A / goose / Hong Kong / ww28 / 2000 (H5N1)), an incomplete coding sequence.

AY059494, gene segment 5 nucleocapsid protein (NP) of influenza A virus (A / duck / Hong Kong / ww381 / 2000 (H5N1)), an incomplete coding sequence.

AY059495, segment 5 gene for the nucleocapsid protein (NP) of influenza A virus (A / duck / Hong Kong / ww461 / 2000 (H5N1)), an incomplete coding sequence.

AY059496, segment 5 gene for the nucleocapsid protein (NP) of influenza A virus (A / goose / Hong Kong / ww491 / 2000 (H5N1)), an incomplete coding sequence.

AY059497, segment 5 gene of the nucleocapsid protein (NP) of influenza A virus (A / duck / Hong Kong / 2986.1 / 2000 (H5N1)), an incomplete coding sequence.

AY059498, segment 5 gene for the nucleocapsid protein (NP) of influenza A virus (A / goose / Hong Kong / 3014.8 / 2000 (H5N1)), an incomplete coding sequence.

AF398419, influenza A virus nucleocapsid protein (NP) gene (A / goose / Hong Kong / 385.3 / 2000 (H5N1)), incomplete coding sequence.

AF398420, influenza A virus nucleocapsid protein (NP) gene (A / goose / Hong Kong / 385.5 / 2000 (H5N1)), incomplete coding sequence.

AF468842, influenza A virus nucleocapsid protein (NP) gene (A / duck / Anyang / AVL-1/2001 (H5N1)), full-length coding sequence.

AF509117, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / FY77 / 01 (H5N1)), full-length coding sequence.

AF509118, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), full-length coding sequence.

AF509119, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / YU563 / 01 (H5N1)), full-length coding sequence.

AY585438, influenza A virus nucleoprotein (NP) mRNA (A / duck / Shanghai / 38/2001 (H5N1)), full-length coding sequence.

AY221548, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / NT873.3 / 01-MB (H5N1)), incomplete coding sequence.

AY221549, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / NT873.3 / 01 (H5N1)), incomplete coding sequence.

AY221550, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / FY150 / 01-MB (H5N1)), incomplete coding sequence.

AY221551, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), incomplete coding sequence.

AY221552, influenza A virus nucleocapsid protein (NP) gene (A / pheasant / Hong Kong / FY155 / 01-MB (HSN1)), incomplete coding sequence.

AY221553, influenza A virus nucleocapsid protein (NP) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), incomplete coding sequence.

AY221554, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / YU822.2 / 01-MB (H5N1)), incomplete coding sequence.

AY221555, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / YU822.2 / 01 (H5N1)), incomplete coding sequence.

AY221556, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / YU552 / 01 (H5N1)), incomplete coding sequence.

AF509120, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), full-length coding sequence.

AF509121, influenza A virus nucleocapsid protein (NP) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), full-length coding sequence.

AF509122, influenza A virus nucleocapsid protein (NP) gene (A / silk chicken / Hong Kong / SF189 / 01 (H5N1)), incomplete coding sequence.

AF509123, influenza A virus nucleocapsid protein (NP) gene (A / quail / Hong Kong / SF203 / 01 (H5N1)), incomplete coding sequence.

AF509124, influenza A virus nucleocapsid protein (NP) gene (A / pigeon / Hong Kong / SF215 / 01 (H5N1)), incomplete coding sequence.

AF509125, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / SF219 / 01 (H5N1)), incomplete coding sequence.

AF509126, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 715.5 / 01 (H5N1)), incomplete coding sequence.

AF509127, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 751.1 / 01 (H5N1)), incomplete coding sequence.

AF509128, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 822.1 / 01 (H5N1)), incomplete coding sequence.

AF509129, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 829.2 / 01 (H5N1)), incomplete coding sequence.

AF509130, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 830.2 / 01 (H5N1)), incomplete coding sequence.

AF509131, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 858.3 / 01 (H5N1)), incomplete coding sequence.

AF509132, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 866.3 / 01 (H5N1)), incomplete coding sequence.

AF509133, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 867.1 / 01 (H5N1)), incomplete coding sequence.

AF509134, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 879.1 / 01 (H5N1)), incomplete coding sequence.

AF509135, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 873.3 / 01 (H5N1)), incomplete coding sequence.

AF509136, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 876.1 / 01 (H5N1)), incomplete coding sequence.

AF509137, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 891.1 / 01 (H5N1)), incomplete coding sequence.

AF509138, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Hong Kong / 893.2 / 01 (H5N1)), incomplete coding sequence.

AF509139, influenza A virus nucleocapsid protein (NP) gene (A / goose / Hong Kong / 76.1 / 01 (H5N1)), full-length coding sequence.

AF509140, influenza A virus nucleocapsid protein (NP) gene (A / goose / Hong Kong / ww100 / 01 (H5N1)), incomplete coding sequence.

AF509141, influenza A virus nucleocapsid protein (NP) gene (A / duck / Hong Kong / 573.4 / 01 (H5N1)), incomplete coding sequence.

AF509142, influenza A virus nucleocapsid protein (NP) gene (A / duck / Hong Kong / 646.3 / 01 (H5N1)), incomplete coding sequence.

AY585424, influenza A virus nucleoprotein (NP) mRNA (A / duck / Guangdong / O1 / 2001 (H5N1)), full-length coding sequence.

AY585422, mRNA of the influenza A virus nucleoprotein (NP) (A / duck / Fujiyan / 17/2001 (H5N1)), full-length coding sequence.

AY585430, influenza A virus nucleoprotein (NP) mRNA (A / duck / Guangxi / 22/2001 (H5N1)), full-length coding sequence.

AY585431, mRNA of the influenza A virus nucleoprotein (NP) (A / duck / Guangxi / 35/2001 (H5N1)), full-length coding sequence.

AY585432, mRNA of the influenza A virus nucleoprotein (NP) (A / duck / Guangxi / 50/2001 (H5N1)), full-length coding sequence.

AY585434, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Shanghai / 08/2001 (H5N1)), full-length coding sequence.

AY585435, influenza A virus nucleoprotein (NP) mRNA (A / duck / Shanghai / 13/2001 (H5N1)), full-length coding sequence.

AY585436, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Shanghai / 35/2002 (H5N1)), full-length coding sequence.

AY585437, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Shanghai / 37/2002 (H5N1)), full-length coding sequence.

AY585433, influenza A virus nucleoprotein (NP) mRNA (A / duck / Guangxi / 53/2002 (H5N1)), full-length coding sequence.

AY585427, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Guangdong / 22/2002 (H5N1)), full-length coding sequence.

AY585420, influenza A virus nucleoprotein (NP) mRNA (A / duck / Fujiyan / 01/2002 (H5N1)), full-length coding sequence.

AY585421, mRNA of influenza A virus nucleoprotein (NP) (A / duck / Fujiyan / 13/2002 (H5N1)), full-length coding sequence.

AY575907, influenza A virus nucleocapsid protein (NP) gene (A / Gs / HK / 739.2 / 02 (H5N1)), incomplete coding sequence.

AY575908, influenza A virus nucleocapsid protein (NP) gene (A / Eg / HK / 757.3 / 02 (H5N1)), incomplete coding sequence.

AY575909, influenza A virus nucleocapsid protein (NP) gene (A / G.H / HK / 793.1 / 02 (H5N1)), incomplete coding sequence.

AY575910, influenza A virus nucleocapsid protein (NP) gene (A / Dk / HK / 821/02 (H5N1)), incomplete coding sequence.

AY575911, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 31.4 / 02 (H5N1)), full-length coding sequence.

AY575912, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 61.9 / 02 (H5N1)), full-length coding sequence.

AY575913, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / YU777 / 02 (H5N1)), incomplete coding sequence.

AY575914, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 96.1 / 02 (H5N1)), incomplete coding sequence.

AY575915, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 409.1 / 02 (H5N1)), incomplete coding sequence.

AY575916, influenza A virus nucleocapsid protein (NP) gene (A / Ph / HK / sv674.15 / 02 (H5N1)), incomplete coding sequence.

DQ023146, mRNA of the nucleoprotein (NP) of influenza A virus A / chicken / sd / 1/02 (H5N1)), a full-length coding sequence.

AY676037, influenza A virus nucleoprotein (NP) gene (A / duck / Hong Kong / 821/02 (H5N1)), full-length coding sequence.

AY651510, influenza A virus nucleocapsid protein (NP) gene (A / Gf / HK / 38/2002 (H5N1)), full-length coding sequence.

AY651511, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 31.2 / 2002 (H5N1)), full-length coding sequence.

AY651512, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 37.4 / 2002 (H5N1)), full-length coding sequence.

AY651513, influenza A virus nucleocapsid protein (NP) gene (A / SCk / HK / YU100 / 2002 (H5N1)), full-length coding sequence.

AY651514, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / YU22 / 2002 (H5N1)), incomplete coding sequence.

AY651521, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 3176.3 / 2002 (H5N1)), incomplete coding sequence.

AY651522, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 3169.1 / 2002 (H5N1)), incomplete coding sequence.

AY651524, influenza A virus nucleocapsid protein (NP) gene (A / feral pigeon / HK / 862.7 / 2002 (H5N1)), incomplete coding sequence.

AY651525, influenza A virus nucleocapsid protein (NP) gene (A / Sparrow / HK / 864/2002 (H5N1)), incomplete coding sequence.

AY651526, influenza A virus nucleocapsid protein (NP) gene (A / gray heron / HK / 861.1 / 2002 (H5N1)), incomplete coding sequence.

AY651527, influenza A virus nucleocapsid protein (NP) gene (A / teal / China / 2978.1 / 2002 (H5N1)), incomplete coding sequence.

AY651523, influenza A virus nucleocapsid protein (NP) gene (A / black-headed gull / HK / 12.1 / 2003 (H5N1)), incomplete coding sequence.

AY651487, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Indonesia / PA / 2003 (H5N1)), incomplete coding sequence.

AY651515, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / 2133.1 / 2003 (H5N1)), incomplete coding sequence.

AY651516, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / NT93 / 2003 (H5N1)), incomplete coding sequence.

AY651517, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / SSP141 / 2003 (H5N1)), incomplete coding sequence.

AY651518, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / WF157 / 2003 (H5N1)), incomplete coding sequence.

AY651519, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / FY157 / 2003 (H5N1)), incomplete coding sequence.

AY651520, influenza A virus nucleocapsid protein (NP) gene (A / Ck / HK / YU324 / 2003 (H5N1)), incomplete coding sequence.

AY651490, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Indonesia / 2A / 2003 (H5N1)), incomplete coding sequence.

AY676038, influenza A virus nucleoprotein (NP) gene (A / egret / Hong Kong / 757.2 / 03 (H5N1)), full-length coding sequence.

AY676039, influenza A virus nucleoprotein (NP) gene (A / chicken / Korea / ES / 03 (H5N1)), full-length coding sequence.

AY676040, influenza A virus nucleoprotein (NP) gene (A / duck / Korea / ESD1 / 03 (H5N1)), full-length coding sequence.

AY651529, influenza A virus nucleoprotein (NP) gene (A / Dk / HN / 5806/2003 (H5N1)), incomplete coding sequence.

AY651532, influenza A virus nucleocapsid protein (NP) gene (A / Ck / ST / 4231/2003 (H5N1)), incomplete coding sequence.

AY651534, influenza A virus nucleocapsid protein (NP) gene (A / Dk / ST / 4003/2003 (H5N1)), incomplete coding sequence.

AY651535, influenza A virus nucleocapsid protein (NP) gene (A / Dk / YN / 6255/2003 (H5N1)), incomplete coding sequence.

AY651536, influenza A virus nucleocapsid protein (NP) gene (A / Dk / YN / 6445/2003 (H5N1)), incomplete coding sequence.

AY651485, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Indonesia / BL / 2003 (H5N1)), incomplete coding sequence.

AY518364, influenza A virus nucleocapsid protein (NP) gene (A / duck / China / E319-2 / 03 (H5N1)), full-length coding sequence.

AY574189, influenza A virus nucleoprotein gene (A / chicken / Vietnam / HD1 / 2004 (H5N1)), incomplete coding sequence.

AY574192, influenza A virus nucleoprotein gene (A / chicken / Vietnam / HD2 / 2004 (H5N1)), incomplete coding sequence.

AJ867076, NP nucleoprotein gene of influenza A virus (A / Hatei / 2004 / (H5N1)), genomic RNA.

AY651486, influenza A virus nucleocapsid protein (NP) gene (A / Dk / Indonesia / MS / 2004 (H5N1)), incomplete coding sequence.

AY590579, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Patom Highlands / Thailand / CU-K2 / 2004 (H5N1)), full-length coding sequence.

AY609313, influenza A virus segment 5 (A / chicken / Guangdong / 174/04 (H5N1)), full length sequence.

AY576929, influenza A virus nucleoprotein segment 5 gene (A / chicken / Vietnam / CM / 2004 (H5N1)), incomplete coding sequence.

AY576931, influenza A virus nucleoprotein segment 5 gene (A / musk duck / Vietnam / MdGL / 2004 (H5N1)), incomplete coding sequence.

AB166863, the influenza A virus nucleoprotein NP gene A (A / chicken / Yamaguchi / 7/2004 (H5N1)), a full-length coding sequence.

AB188817, the influenza A virus nucleoprotein NP gene A (A / chicken / Oita / 8/2004 (H5N1)), a full-length coding sequence.

AY651537, influenza A virus nucleocapsid protein (NP) gene (A / Ck / YN / 374/2004 (H5N1)), incomplete coding sequence.

AY651538, influenza A virus nucleocapsid protein (NP) gene (A / Ck / YN / 115/2004 (H5N1)), incomplete coding sequence.

AY653196, segment 5 of influenza A virus (A / chicken / Zhilin / 9/2004 (H5N1)), full length sequence.

AY651533, influenza A virus nucleocapsid protein (NP) gene (A / Ph / ST / 44/2004 (H5N1)), incomplete coding sequence.

AY651530, influenza A virus nucleocapsid protein (NP) gene (A / Dk / HN / 303/2004 (H5N1)), incomplete coding sequence.

AY651531, influenza A virus nucleocapsid protein (NP) gene (A / Dk / HN / 101/2004 (H5N1)), incomplete coding sequence.

AY684707, influenza A virus nucleoprotein (NP) gene (A / chicken / Hubei / 327/2004 (H5N1)), full-length coding sequence.

AY737290, influenza A virus segment 5 (A / chicken / Guangdong / 191/04 (H5N1)), full length sequence.

AY737297, influenza A virus segment 5 (A / chicken / Guangdong / 178/04 (H5N1)), full length sequence.

AY737305, influenza A virus segment 5 (A / duck / Guangdong / 173/04 (H5N1)), full length sequence.

AY770081, influenza A virus nucleoprotein (NP) gene (A / chicken / Hubei / 489/2004 (H5N1)), full-length coding sequence.

AY770996, the influenza A virus nucleoprotein gene (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)), an incomplete coding sequence.

AY818139, influenza A virus nucleoprotein NP gene (A / chicken / Vietnam / C58 / 04 (H5N1)), full-length coding sequence.

AY818140, influenza A virus nucleoprotein NP gene A (A / quail / Vietnam / 36/04 (H5N1)), full-length coding sequence.

AY856864, influenza A virus segment 5 (A / duck / Shandu / 093/2004 (H5N1)), full length sequence.

AB189046, the influenza A virus nucleoprotein NP gene A (A / chicken / Kyoto / 3/2004 (H5N1)), a full-length coding sequence.

AB189054, the influenza A virus nucleoprotein NP gene A (A / raven / Kyoto / 53/2004 (H5N1)), a full-length coding sequence.

AB189062, the nucleoprotein NP gene of influenza A virus (A / raven / Osaka / 102/2004 (H5N1)), a full-length coding sequence.

AY651491, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Thailand / 1/2004 (H5N1)), incomplete coding sequence.

AY651492, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Thailand / 73/2004 (H5N1)), incomplete coding sequence.

AY651493, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Thailand / 9.1 / 2004 (H5N1)), incomplete coding sequence.

AY651494, influenza A virus nucleocapsid protein (NP) gene (A / Qa / Thailand / 57/2004 (H5N1)), incomplete coding sequence.

AY651495, influenza A virus nucleocapsid protein (NP) gene (A / avian / Thailand / 3.1 / 2004 (H5N1)), incomplete coding sequence.

AY651496, influenza A virus nucleocapsid protein (NP) gene (A / Dk / Thailand / 71.1 / 2004 (H5N1)), incomplete coding sequence.

AY651497, influenza A virus nucleocapsid protein (NP) gene (A / Gs / Thailand / 79/2004 (H5N1)), incomplete coding sequence.

AY651502, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / 33/2004 (H5N1)), incomplete coding sequence.

AY651503, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / 35/2004 (H5N1)), incomplete coding sequence.

AY651504, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / 36/2004 (H5N1)), incomplete coding sequence.

AY651505, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / 37/2004 (H5N1)), incomplete coding sequence.

AY651506, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / 38/2004 (H5N1)), incomplete coding sequence.

AY651507, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / 39/2004 (H5N1)), incomplete coding sequence.

AY651508, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Vietnam / C57 / 2004 (H5N1)), incomplete coding sequence.

AY651509, influenza A virus nucleocapsid protein (NP) gene (A / Dk / Vietnam / 11/2004 (H5N1)), incomplete coding sequence.

AY651488, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Indonesia / 4/2004 (H5N1)), incomplete coding sequence.

AY651489, influenza A virus nucleocapsid protein (NP) gene (A / Ck / Indonesia / 5/2004 (H5N1)), incomplete coding sequence.

AY651528, influenza A virus nucleocapsid protein (NP) gene (A / Peregrine Falcon / HK / D0028 / 2004 (H5N1)), incomplete coding sequence.

M22573, RNA of nucleoprotein (segment 5) of influenza A virus / duck / Hong Kong / 7/75 (H3N2).

AY180555, influenza A virus nucleoprotein (NP) gene (A / chicken / Nanhan / 3-120 / 2001 (H3N2)), incomplete coding sequence.

AY779261, influenza A virus nucleoprotein (NP) gene (A / turkey / North Carolina / 12344/03 (H3N2)), incomplete coding sequence.

AY779262, influenza A virus nucleoprotein (NP) gene (A / turkey / Minnesota / 764-2 / 03 (H3N2)), incomplete coding sequence.

AY862655, influenza A virus nucleocapsid protein (NP) gene (A / chicken / Korea / S6 / 03 (H3N2)), incomplete coding sequence.

AY862656, influenza A virus nucleocapsid protein (NP) gene (A / duck / Korea / S7 / 03 (H3N2)), incomplete coding sequence.

AY862657, influenza A virus nucleocapsid protein (NP) gene (A / duck / Korea / S8 / 03 (H3N2)), incomplete coding sequence.

AY862658, influenza A virus nucleocapsid protein (NP) gene (A / duck / Korea / S9 / 03 (H3N2)), incomplete coding sequence.

AY862659, influenza A virus nucleocapsid protein (NP) gene (A / duck / Korea / S10 / 03 (H3N2)), incomplete coding sequence.

AY862660, influenza A virus nucleocapsid protein (NP) gene (A / pigeon / Korea / S11 / 03 (H3N2)), incomplete coding sequence.

D00050, influenza A virus nucleoprotein gene, full-length coding sequence.

M14921, RNA of the nucleoprotein (segment 5) of influenza A virus / Mallard / NY / 6750/78 (H2N2), full-length coding sequence.

AY422026, influenza A virus nucleoprotein gene, (A / duck / Hokkaido / 95/01 (H2N2)), incomplete coding sequence.

U49093, influenza A virus nucleoprotein (NP) mRNA, incomplete coding sequence.

M22574, RNA of the nucleoprotein (segment 5) of influenza A virus / duck / Bavaria / 2/77 (H1N1).

M76603, mRNA of influenza A virus / turkey / England / 647/77 (H1N1), full-length coding sequence.

M63783, influenza A virus nucleoprotein mRNA / duck / Australia / 749/80 (H1N1), full-length coding sequence.

M63778, influenza A virus nucleoprotein mRNA / Turkey / Minnesota / 1661/81 (H1N1), full-length coding sequence.

Z26855, Type A influenza virus nucleoprotein NP gene.

M76609, mRNA of influenza A virus / turkey / North Carolina / 1790/88 (H1N1), full-length coding sequence.

Z26857, Type A influenza virus nucleoprotein NP gene.

AF213905, influenza A virus nucleoprotein (NP) segment 5 gene (A / Mallard / Italy / 24/95 (H1N1)), incomplete coding sequence.

AF213906, influenza A virus nucleoprotein (NP) segment 5 gene (A / chicken / Italy / 24/95 (H1N1)), incomplete coding sequence.

AY633215, influenza A virus nucleoprotein (NP) gene (A / Mallard / Alberta / 211/98 (H1N1)), full-length coding sequence.

AY180543, influenza A virus nucleoprotein (NP) gene (A / quail / Nanhan / 12-340 / 2000 (H1N1)), incomplete coding sequence.

The sequences used in the analysis of the main polymerase protein 1 (PB1) of influenza A virus

AY633218, gene of the RNA-dependent RNA polymerase subunit P1 (PB1) of influenza A virus (A / mallard / Alberta / 211/98 (H1N1)), incomplete coding sequence.

U48284, mRNA polymerase (PB1) of influenza A virus, incomplete coding sequence.

AY180855, gene for the polymerase subunit of PB1 (PB1) strain of the influenza virus A / quail / Nanhan / 12-340 / 2000 (H1N1), an incomplete coding sequence.

AY422038, gene of the polymerase subunit of PB1 (PB1) strain of influenza A virus (A / duck / Hokkaido / 95/01 (H2N2)), an incomplete coding sequence.

M25926, influenza A virus PB1 gene / Mallard / New York / 6750/78 (H2N2), full-length coding sequence.

AY180871, gene for the polymerase subunit of PB1 (PB1) strain of the influenza A virus / chicken / Nanhan / 3-120 / 2001 (H3N2), an incomplete coding sequence.

AY779265, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)), an incomplete coding sequence.

AY779266, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)), an incomplete coding sequence.

AY862703, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S6 / 03 (H3N2)), incomplete coding sequence.

AY862704, gene PB1 (PB1) of influenza A virus (A / duck / Korea / S7 / 03 (H3N2)), incomplete coding sequence.

AY862705, gene PB1 (PB1) of influenza A virus (A / duck / Korea / S8 / 03 (H3N2)), incomplete coding sequence.

AY862706, gene PB1 (PB1) of influenza A virus (A / duck / Korea / S9 / 03 (H3N2)), incomplete coding sequence.

AY862707, gene PB1 (PB1) of influenza A virus (A / duck / Korea / S10 / 03 (H3N2)), an incomplete coding sequence.

AY862708, gene PB1 (PB1) of influenza A virus (A / pigeon / Korea / S11 / 03 (H3N2)), incomplete coding sequence.

AF213911, gene of segment 8 of the influenza A virus polymerase PB1 polymerase protein (A / chicken / Italy / 5945/95 (H3N2)), incomplete coding sequence.

AB166860, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)), a full-length coding sequence.

AB188814, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Oita / 8/2004 (H5N1)), a full-length coding sequence.

AF398423, influenza A virus polymerase (PB1) gene (A / goose / Hong Kong / 385.3 / 2000 (H5N1)), incomplete coding sequence.

AF398424, influenza A virus polymerase (PB1) gene (A / goose / Hong Kong / 385.5 / 2000 (H5N1)), incomplete coding sequence.

AF468839, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Anyang / AVL-1/2001 (H5N1)), a full-length coding sequence.

AF509169, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / FY77 / 01 (H5N1)), incomplete coding sequence.

AF509170, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), incomplete coding sequence.

AF509171, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / YU563 / 01 (H5N1)), incomplete coding sequence.

AF509172, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), incomplete coding sequence.

AF509173, influenza A virus polymerase (PB1) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), incomplete coding sequence.

AF509174, influenza A virus polymerase (PB1) gene (A / silk chicken / Hong Kong / SF189 / 01 (H5N1)), incomplete coding sequence.

AF509175, influenza A virus polymerase (PB1) gene (A / quail / Hong Kong / SF203 / 01 (H5N1)), incomplete coding sequence.

AF509176, influenza A virus polymerase (PB1) gene (A / pigeon / Hong Kong / SF215 / 01 (H5N1)), incomplete coding sequence.

AF509177, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / SF219 / 01 (H5N1)), incomplete coding sequence.

AF509178, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 715.5 / 01 (H5N1)), incomplete coding sequence.

AF509179, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 751.1 / 01 (H5N1)), incomplete coding sequence.

AF509180, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 822.1 / 01 (H5N1)), incomplete coding sequence.

AF509181, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 829.2 / 01 (H5N1)), incomplete coding sequence.

AF509182, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 830.2 / 01 (H5N1)), incomplete coding sequence.

AF509183, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 858.3 / 01 (H5N1)), incomplete coding sequence.

AF509184, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 866.3 / 01 (H5N1)), incomplete coding sequence.

AF509185, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 867.1 / 01 (H5N1)), incomplete coding sequence.

AF509186, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 879.1 / 01 (H5N1)), incomplete coding sequence.

AF509187, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 873.3 / 01 (H5N1)), incomplete coding sequence.

AF509188, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 876.1 / 01 (H5N1)), incomplete coding sequence.

AF509189, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 891.1 / 01 (H5N1)), incomplete coding sequence.

AF509190, influenza A virus polymerase (PB1) gene (A / chicken / Hong Kong / 893.2 / 01 (H5N1)), incomplete coding sequence.

AF509191, influenza A virus polymerase (PB1) gene (A / goose / Hong Kong / 76.1 / 01 (H5N1)), incomplete coding sequence.

AF509192, influenza A virus polymerase (PB1) gene (A / goose / Hong Kong / ww100 / 01 (H5N1)), incomplete coding sequence.

AF509193, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 573.4 / 01 (H5N1)), incomplete coding sequence.

AF509194, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 646.3 / 01 (H5N1)), incomplete coding sequence.

AY035888, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / goose / Guangdong / 3/97 (H5N1)), a full-length coding sequence.

AY059513, influenza A virus polymerase (PB1) segment 2 gene (A / goose / Hong Kong / ww26 / 2000 (H5N1)), incomplete coding sequence.

AY059514, influenza A virus polymerase (PB1) segment 2 gene (A / goose / Hong Kong / ww28 / 2000 (H5N1)), incomplete coding sequence.

AY059515, influenza A virus polymerase (PB1) segment 2 gene (A / duck / Hong Kong / ww381 / 2000 (H5N1)), incomplete coding sequence.

AY059516, influenza A virus polymerase (PB1) segment 2 gene (A / duck / Hong Kong / ww461 / 2000 (H5N1)), incomplete coding sequence.

AY059517, influenza A virus polymerase (PB1) segment 2 gene (A / goose / Hong Kong / ww491 / 2000 (H5N1)), incomplete coding sequence.

AY059518, influenza A virus polymerase (PB1) segment 2 gene (A / duck / Hong Kong / 2986.1 / 2000 (H5N1)), incomplete coding sequence.

AY059519, influenza A virus polymerase (PB1) segment 2 gene (A / goose / Hong Kong / 3014.8 / 2000 (H5N1)), incomplete coding sequence.

AY221575, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / NT873.3 / 01-MB (H5N1)), an incomplete coding sequence.

AY221576, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / NT873.3 / 01 (H5N1)), an incomplete coding sequence.

AY221577, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / FY150 / 01-MB (H5N1)), an incomplete coding sequence.

AY221578, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / FY150 / 01 (H5N1)), an incomplete coding sequence.

AY221579, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / pheasant / Hong Kong / FY155 / 01-MB (H5N1)), an incomplete coding sequence.

AY221580, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), an incomplete coding sequence.

AY221581, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / YU822.2 / 01-MB (H5N1)), an incomplete coding sequence.

AY221582, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / YU822.2 / 01 (H5N1)), an incomplete coding sequence.

AY221583, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / YU562 / 01 (H5N1)), an incomplete coding sequence.

AY518366, gene for the polymerase subunit of the PB1 (PB1) influenza A virus (A / duck / China / E319-2 / 03 (H5N1)), a full-length coding sequence.

AY576394, influenza A virus polymerase (PB1) gene (A / Gs / HK / 739.2 / 02 (H5N1)), incomplete coding sequence.

AY576395, influenza A virus polymerase (PB1) gene (A / Eg / HK / 757.3 / 02 (H5N1)), incomplete coding sequence.

AY576396, influenza A virus polymerase (PB1) gene (A / G.H / HK / 793.1 / 02 (H5N1)), incomplete coding sequence.

AY576397, influenza A virus polymerase (PB1) gene (A / Dk / HK / 821/02 (H5N1)), full-length coding sequence.

AY576398, influenza A virus polymerase (PB1) gene (A / Ck / HK / 31.4 / 02 (H5N1)), incomplete coding sequence.

AY576399, influenza A virus polymerase (PB1) gene (A / Ck / HK / 61.9 / 02 (H5N1)), incomplete coding sequence.

AY576400, influenza A virus polymerase (PB1) gene (A / Ck / HK / YU777 / 02 (H5N1)), incomplete coding sequence.

AY576401, influenza A virus polymerase (PB1) gene (A / Ck / HK / 96.1 / 02 (H5N1)), incomplete coding sequence.

AY576402, influenza A virus polymerase (PB1) gene (A / Ck / HK / 409.1 / 02 (H5N1)), incomplete coding sequence.

AY576403, influenza A virus polymerase (PB1) gene (A / Ph / HK / 674.15 / 02 (H5N1)), incomplete coding sequence.

AY585483, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Fuyang / 01/2002 (H5N1)), a full-length coding sequence.

AY585484, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Fuyang / 13/2002 (H5N1)), a full-length coding sequence.

AY585485, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Fuyang / 17/2001 (H5N1)), a full-length coding sequence.

AY585486, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Fuyang / 19/2000 (H5N1)), a full-length coding sequence.

AY585487, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)), full-length coding sequence.

AY585488, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)), full-length coding sequence.

AY585489, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)), full-length coding sequence.

AY585490, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)), full-length coding sequence.

AY585491, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)), full-length coding sequence.

AY585492, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)), full-length coding sequence.

AY585493, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)), a full-length coding sequence.

AY585494, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)), a full-length coding sequence.

AY585495, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)), a full-length coding sequence.

AY585496, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)), full-length coding sequence.

AY585497, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Shanghai / 08/2001 (H5N1)), a full-length coding sequence.

AY585498, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Shanghai / 13/2001 (H5N1)), a full-length coding sequence.

AY585499, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Shanghai / 35/2002 (H5N1)), a full-length coding sequence.

AY585500, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Shanghai / 37/2002 (H5N1)), a full-length coding sequence.

AY585501, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Shanghai / 38/2001 (H5N1)), a full-length coding sequence.

AY585502, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Zheyan / 11/2000 (H5N1)), full-length coding sequence.

AY585503, mRNA of the polymerase base protein 1 (PB1) of influenza A virus (A / duck / Zheyan / 52/2000 (H5N1)), full-length coding sequence.

AY590582, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Patom Highlands / Thailand / CU-K2 / 2004 (H5N1)), a full-length coding sequence.

AY609310, influenza A virus segment 2 (A / chicken / Guangdong / 174/04 (H5N1)), full length sequence.

AY651651, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)), an incomplete coding sequence.

AY651652, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)), an incomplete coding sequence.

AY651653, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)), an incomplete coding sequence.

AY651654, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)), an incomplete coding sequence.

AY651655, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / chicken / Indonesia / 2A / 2003 (H5N1)), an incomplete coding sequence.

AY651656, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)), an incomplete coding sequence.

AY651657, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)), an incomplete coding sequence.

AY651658, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)), an incomplete coding sequence.

AY651659, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)), an incomplete coding sequence.

AY651660, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)), an incomplete coding sequence.

AY651661, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / avian / Thailand / 3.1 / 2004 (H5N1)), an incomplete coding sequence.

AY651662, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)), an incomplete coding sequence.

AY651663, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)), an incomplete coding sequence.

AY651668, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)), an incomplete coding sequence.

AY651669, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)), an incomplete coding sequence.

AY651670, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)), an incomplete coding sequence.

AY651671, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)), an incomplete coding sequence.

AY651672, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)), an incomplete coding sequence.

AY651673, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)), an incomplete coding sequence.

AY651674, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)), an incomplete coding sequence.

AY651675, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)), an incomplete coding sequence.

AY651676, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Gf / HK / 38/2002 (H5N1)), an incomplete coding sequence.

AY651677, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)), an incomplete coding sequence.

AY651678, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)), an incomplete coding sequence.

AY651679, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)), an incomplete coding sequence.

AY651680, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)), an incomplete coding sequence.

AY651681, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)), an incomplete coding sequence.

AY651682, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)), an incomplete coding sequence.

AY651683, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)), an incomplete coding sequence.

AY651684, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)), an incomplete coding sequence.

AY651685, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)), an incomplete coding sequence.

AY651686, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)), an incomplete coding sequence.

AY651687, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)), an incomplete coding sequence.

AY651688, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)), an incomplete coding sequence.

AY651689, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / black-headed gull / HK / 12.1 / 2003 (H5N1)), an incomplete coding sequence.

AY651690, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / feral pigeon / HK / 862.7 / 2002 (H5N1)), an incomplete coding sequence.

AY651691, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / gray heron / HK / 861.1 / 2002 (H5N1)), an incomplete coding sequence.

AY651692, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / tree sparrow / HK / 864/2002 (H5N1)), an incomplete coding sequence.

AY651693, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)), an incomplete coding sequence.

AY651694, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)), an incomplete coding sequence.

AY651695, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / HN / 5806/2003 (H5N1)), an incomplete coding sequence.

AY651696, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / ST / 4003/2003 (H5N1)), an incomplete coding sequence.

AY651697, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / ST / 4231/2003 (H5N1)), an incomplete coding sequence.

AY651698, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / YN / 6255/2003 (H5N1)), an incomplete coding sequence.

AY651699, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / YN / 6445/2003 (H5N1)), an incomplete coding sequence.

AY651700, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ph / ST / 44/2004 (H5N1)), an incomplete coding sequence.

AY651701, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / HN / 303/2004 (H5N1)), an incomplete coding sequence.

AY651702, gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Dk / HN / 101/2004 (H5N1)), an incomplete coding sequence.

AY651703, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / YN / 374/2004 (H5N1)), an incomplete coding sequence.

AY651704, the gene for the polymerase base subunit 1 (PB1) of influenza A virus (A / Ck / YN / 115/2004 (H5N1)), an incomplete coding sequence.

AY653199, segment 2 of influenza A virus (A / chicken / Zhilin / 9/2004 (H5N1)), full length sequence.

AY676025, the gene for the polymerase base protein 1 (PB1) of influenza A strain A (A / duck / Hong Kong / 821/02 (H5N1)), a full-length coding sequence.

AY676026, the gene for the polymerase base protein 1 (PB1) of influenza A strain A (A / egret / Hong Kong / 757.2 / 03 (H5N1)), a full-length coding sequence.

AY676027, gene for the polymerase base protein 1 (PB1) of influenza A strain A (A / chicken / Korea / ES / 03 (H5N1)), full-length coding sequence.

AY676028, the gene for the polymerase base protein 1 (PB1) of influenza A strain A (A / duck / Korea / ESD1 / 03 (H5N1)), a full-length coding sequence.

AY684704, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)), a full-length coding sequence.

AY737287, influenza A virus segment 2 (A / chicken / Guangdong / 191/04 (H5N1)), full length sequence.

AY737294, influenza A virus segment 2 (A / chicken / Guangdong / 178/04 (H5N1)), full length sequence.

AY737302, influenza A virus segment 2 (A / duck / Guangdong / 173/04 (H5N1)), full length sequence.

AY770083, gene for non-functional polymerase base protein 1 of influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)), full-sized sequence.

AY770994, influenza A virus polymerase base protein 1 gene (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)), incomplete coding sequence.

AY818130, influenza A virus polymerase protein PB1 gene (A / chicken / Vietnam / C58 / 04 (H5N1)), full-length coding sequence.

AY818131, influenza A virus polymerase protein PB1 gene (A / quail / Vietnam / 36/04 (H5N1)), full-length coding sequence.

AY856862, segment 2 of influenza A virus (A / duck / Shandu / 093/2004 (H5N1)), full length sequence.

AB188822, the gene for the polymerase base protein 1 of influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)), a full-length coding sequence.

AB189051, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)), a full-length coding sequence.

AB189060, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / raven / Osaka / 102/2004 (H5N1)), a full-length coding sequence.

AF046085, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / 220/97 (H5N1)), a full-length coding sequence.

AF098590, influenza A virus PB1 (PB1) protein gene (A / chicken / Hong Kong / 258/97 (H5N1)), incomplete coding sequence.

AF098591, the influenza A virus PB1 (PB1) protein gene (A / chicken / Hong Kong / y388 / 97 (H5N1)), an incomplete coding sequence.

AF098592, influenza A virus PB1 (PB1) protein gene (A / chicken / Hong Kong / 728/97 (H5N1)), incomplete coding sequence.

AF098593, the influenza A virus PB1 (PB1) protein gene (A / chicken / Hong Kong / 786/97 (H5N1)), an incomplete coding sequence.

AF098594, influenza A virus PB1 (PB1) protein gene (A / chicken / Hong Kong / 915/97 (H5N1)), incomplete coding sequence.

AF098595, influenza A virus PB1 (PB1) protein gene (A / duck / Hong Kong / p46 / 97 (H5N1)), incomplete coding sequence.

AF098596, influenza A virus PB1 (PB1) protein gene (A / duck / Hong Kong / y283 / 97 (H5N1)), incomplete coding sequence.

AF098598, influenza A virus PB1 (PB1) protein gene (A / goose / Hong Kong / w355 / 97 (H5N1)), incomplete coding sequence.

AF144301, influenza A virus polymerase (PB1) gene (A / goose / Guangdong / 1/96 (H5N1)), full-length coding sequence.

AF216716, influenza A virus polymerase base protein 1 gene (A / environment / Hong Kong / 437-4 / 99 (H5N1)), full-length coding sequence.

AF216724, influenza A virus polymerase base protein 1 gene (A / environment / Hong Kong / 437-6 / 99 (H5N1)), full-length coding sequence.

AF216732, influenza A virus polymerase base protein 1 gene (A / environment / Hong Kong / 437-8 / 99 (H5N1)), full-length coding sequence.

AF216740, influenza A virus polymerase base protein 1 gene (A / environment / Hong Kong / 437-10 / 99 (H5N1)), full-length coding sequence.

AY303663, the gene for the polymerase base protein 1 of influenza A virus (A / chicken / Chile / 176822/02 (H7N3)), a full-length coding sequence.

AY303664, influenza A virus polymerase base protein 1 gene (A / chicken / Chile / 4957/02 (H7N3)), incomplete coding sequence.

AY586435, influenza A virus PB1 gene (A / turkey / Italy / 214845/02 (H7N3)), incomplete coding sequence.

AY586436, influenza A virus PB1 gene (A / turkey / Italy / 220158/2002 (H7N3)), incomplete coding sequence.

AY586437, influenza A virus PB1 gene (A / Mallard / Italy / 33/01 (H7N3)), incomplete coding sequence.

AY586438, influenza A virus PB1 gene (A / Mallard / Italy / 43/01 (H7N3)), incomplete coding sequence.

AY616765, gene for the polymerase subunit of the PB1 (PB1) influenza A virus (A / chicken / British Columbia / 04 (H7N3)), a full-length coding sequence.

AY646084, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / British Columbia / GSC_man_B / 04 (H7N3)), a full-length coding sequence.

AY648293, gene for the polymerase subunit of the PB1 (PB1) virus of influenza A (A / GSC_ chicken_B / British Columbia / 04 (H7N3)), a full-length coding sequence.

AY653039, gene for the polymerase subunit of the PB1 (PB1) virus of influenza A (A / GSC_ chicken / British Columbia / 04 (H7N3)), a full-length coding sequence.

AJ620348, influenza A virus R1 polymerase PB1 gene (A / chicken / Germany / R28 / 03 (H7N7)), genomic RNA.

AY340080, influenza A virus polymerase (PB1) gene (A / Netherlands / 124/03 (H7N7)), incomplete coding sequence.

AY340081, influenza A virus polymerase (PB1) gene (A / Netherlands / 126/03 (H7N7)), incomplete coding sequence.

AY340082, influenza A virus polymerase (PB1) gene (A / Netherlands / 127/03 (H7N7)), incomplete coding sequence.

AY340083, influenza A virus polymerase (PB1) gene (A / Netherlands / 219/03 (H7N7)), full-length coding sequence.

AY340084, influenza A virus polymerase (PB1) gene (A / Netherlands / 033/03 (H7N7)), full-length coding sequence.

AY340085, influenza A virus polymerase (PB1) gene (A / chicken / Netherlands / 1/03 (H7N7)), full-length coding sequence.

AB049155, gene PB1 of the polymerase base protein 1 of influenza A virus (A / parrot / Chiba / 1/97 (H9N2)), full-length coding sequence.

AB049156, gene PB1 of the polymerase base protein 1 of influenza A virus (A / parrot / Narita / 92A / 98 (H9N2)), full-length coding sequence.

AF508618, gene segment 2 polymerase PB1 (PB1) of influenza A virus (A / ostrich / South Africa / 9508103/95 (H9N2)), an incomplete coding sequence.

AF508619, segment 2 gene of polymerase PB1 (PB1) of influenza A virus (A / chicken / Pakistan / 4/99 (H9N2)), incomplete coding sequence.

AF508620, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Pakistan / 5/99 (H9N2)), an incomplete coding sequence.

AF508621, gene segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Germany / R45 / 98 (H9N2)), an incomplete coding sequence.

AF508622, gene segment 2 polymerase PB1 (PB1) of influenza A virus (A / duck / Germany / 113/95 (H9N2)), an incomplete coding sequence.

AF508623, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Iran / 11T / 99 (H9N2)), an incomplete coding sequence.

AF508624, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Saudi Arabia / 532/99 (H9N2)), an incomplete coding sequence.

AF508625, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / pheasant / Ireland / PV18 / 97 (H9N2)), incomplete coding sequence.

AF508626, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Korea / 99029/99 (H9N2)), an incomplete coding sequence.

AF508627, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Beijin / 8/98 (H9N2)), full-length coding sequence.

AF508628, gene segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Guangdong / 10/00 (H9N2)), an incomplete coding sequence.

AF508629, influenza A virus polymerase segment PB1 (PB1) segment 2 gene (A / chicken / Guangdong / 11/97 (H9N2)), full-length coding sequence.

AF508630, segment 2 gene of polymerase PB1 (PB1) of influenza A virus (A / chicken / Hebei / 4/98 (H9N2)), full-length coding sequence.

AF508631, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Heylonyan / 10/97 (H9N2)), an incomplete coding sequence.

AF508632, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Henan / 62/00 (H9N2)), full-length coding sequence.

AF508633, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Ningxia / 5/99 (H9N2)), full-length coding sequence.

AF508634, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Xihuan / 5/97 (H9N2)), an incomplete coding sequence.

AF508635, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Shandu / 6/96 (H9N2)), an incomplete coding sequence.

AF508636, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Shiyazhuan / 2/99 (H9N2)), full-length coding sequence.

AF508637, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / chicken / Schenzen / 9/97 (H9N2)), full-length coding sequence.

AF508638, gene of segment 2 polymerase PB1 (PB1) of influenza A virus (A / duck / Nanyang / 1/97 (H9N2)), full-length coding sequence.

AF508639, gene 2 segment polymerase PB1 (PB1) of influenza A virus (A / quail / Shanghai / 8/96 (H9N2)), full-length coding sequence.

AF523427, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 830/00 (H9N2)), incomplete coding sequence.

AF523428, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 2102/00 (H9N2)), incomplete coding sequence.

AF523429, gene for segment 2 polymerase PB1 (PB1) of influenza A virus (A / duck / Shantu / 1043/00 (H9N2)), an incomplete coding sequence.

AF523430, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 2134/00 (H9N2)), incomplete coding sequence.

AF523431, influenza A virus polymerase (PB1) gene (A / wild duck / Shantu / 4808/01 (H9N2)), incomplete coding sequence.

AF523432, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 2144/00 (H9N2)), incomplete coding sequence.

AF523433, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 2143/00 (H9N2)), incomplete coding sequence.

AF523434, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 1796/00 (H9N2)), incomplete coding sequence.

AF523435, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 2088/01 (H9N2)), incomplete coding sequence.

AF523436, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 1881/00 (H9N2)), incomplete coding sequence.

AF523437, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 366/78 (H9N2)), incomplete coding sequence.

AF523438, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 552/79 (H9N2)), incomplete coding sequence.

AF523439, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 86/76 (H9N2)), incomplete coding sequence.

AF523440, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 289/78 (H9N2)), incomplete coding sequence.

AF523441, influenza A virus polymerase (PB1) gene (A / duck / Hong Kong / 610/79 (H9N2)), incomplete coding sequence.

AF523442, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 1605/01 (H9N2)), incomplete coding sequence.

AF523443, influenza A virus polymerase (PB1) gene (A / duck / Shantu / 1042/00 (H9N2)), incomplete coding sequence.

AF536659, influenza A virus PB1 gene (A / chicken / Beijin / 1/95 (H9N2)), incomplete coding sequence.

AF536660, influenza A virus PB1 gene (A / chicken / Beijin / 2/97 (H9N2)), incomplete coding sequence.

AF536661, influenza A virus PB1 gene (A / chicken / Beijin / 3/99 (H9N2)), incomplete coding sequence.

AF536662, influenza A virus PB1 gene (A / chicken / Guangdong / 97 (H9N2)), incomplete coding sequence.

AF536663, influenza A virus PB1 gene (A / chicken / Hebei / 1/96 (H9N2)), incomplete coding sequence.

AF536664, influenza A virus PB1 gene (A / chicken / Hebei / 2/98 (H9N2)), incomplete coding sequence.

AF536665, influenza A virus PB1 gene (A / chicken / Hebei / 3/98 (H9N2)), incomplete coding sequence.

AF536666, influenza A virus PB1 gene (A / chicken / Henan / 98 (H9N2)), incomplete coding sequence.

AF536667, influenza A virus PB1 gene (A / chicken / Liaony / 99 (H9N2)), incomplete coding sequence.

AF536668, influenza A virus PB1 gene (A / chicken / Shandu / 98 (H9N2)), incomplete coding sequence.

AJ291396, influenza A virus PB1 polymerase PB1 gene (A / chicken / Pakistan / 2/99 (H9N2)), genomic RNA.

AJ427862, incomplete pb1 gene of influenza A virus polymerase PB1 protein (A / quail / Hong Kong / FY298 / 00 (H9N2)), genomic RNA

AY180840, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / pigeon / Nanhan / 7-058 / 2000 (H9N2), an incomplete coding sequence.

AY180843, gene of the polymerase subunit PB1 (PB1) of influenza virus strain A / quail / Nanhan / 2-0460 / 2000 (H9N2), an incomplete coding sequence.

AY180844, gene of the polymerase subunit PB1 (PB1) of influenza virus strain A / pigeon / Nanhan / 2-0461 / 2000 (H9N2), an incomplete coding sequence.

AY180851, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / pigeon / Nanhan / 11-145 / 2000 (H9N2), an incomplete coding sequence.

AY180852, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / duck / Nanhan / 11-197 / 2000 (H9N2), an incomplete coding sequence.

AY180854, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / duck / Nanhan / 11-290 / 2000 (H9N2), an incomplete coding sequence.

AY180856, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / duck / Nanhan / 1-0070 / 2000 (H9N2), an incomplete coding sequence.

AY180866, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / duck / Nanhan / 7-092 / 2000 (H9N2), an incomplete coding sequence.

AY180867, gene of the polymerase subunit PB1 (PB1) of influenza virus strain A / chicken / Nanhan / 1-0016 / 2000 (H9N2), an incomplete coding sequence.

AY180873, gene of the polymerase subunit of PB1 (PB1) of influenza virus strain A / chicken / Nanhan / 4-010 / 2000 (H9N2), an incomplete coding sequence.

AY180874, gene of the polymerase subunit of PB1 (PB1) of the influenza virus strain A / chicken / Nanhan / 4-301 / 2001 (H9N2), an incomplete coding sequence.

AY180875, gene of the polymerase subunit of PB1 (PB1) of influenza virus strain A / chicken / Nanhan / 4-361 / 2001 (H9N2), an incomplete coding sequence.

AY180892, gene of the polymerase subunit PB1 (PB1) of influenza virus strain A / quail / Nanhan / 4-040 / 2000 (H9N2), an incomplete coding sequence.

AY180897, gene for the polymerase subunit PB1 (PB1) of the influenza A strain / wild duck / Nanhan / 2-0480 / 2000 (H9N2), incomplete coding sequence.

AY180900, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / duck / Nanhan / 10-389 / 2000 (H9N2), an incomplete coding sequence.

AY180901, gene of the polymerase subunit PB1 (PB1) of the influenza virus strain A / duck / Nanhan / 11-392 / 2000 (H9N2), an incomplete coding sequence.

AY253751, the gene for the polymerase base protein 1 (PB1) of influenza A strain A (A / chicken / Shanghai / F / 98 (H9N2)), a full-length coding sequence.

AY307947, gene for the polymerase subunit (PB1) of influenza A virus (A / chicken / Beijin / 1/00 (H9N2)), an incomplete coding sequence.

AY307948, gene of the polymerase subunit (PB1) of influenza A virus (A / chicken / Hebei / 1/01 (H9N2)), an incomplete coding sequence.

AY633170, gene of the RNA-dependent RNA polymerase subunit P1 (PB1) of influenza A virus (A / mallard / Alberta / 17/91 (H9N2)), incomplete coding sequence.

AY633282, gene of the RNA-dependent RNA polymerase subunit P1 (PB1) of influenza A virus (A / mallard / Alberta / 321/88 (H9N2)), incomplete coding sequence.

AY633298, gene of the RNA-dependent RNA polymerase P1 (PB1) of influenza A virus (A / mallard / Alberta / 11/91 (H9N2)), incomplete coding sequence.

AY664774, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)), an incomplete coding sequence.

AY664775, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)), an incomplete coding sequence.

AY664776, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)), an incomplete coding sequence.

AY664777, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)), an incomplete coding sequence.

AY664778, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)), an incomplete coding sequence.

AY664779, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)), an incomplete coding sequence.

AY664780, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / Guinea fowl / Hong Kong / NT101 / 03 (H9N2)), an incomplete coding sequence.

AY664781, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)), an incomplete coding sequence.

AY664782, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / SF1 / 03 (H9N2)), an incomplete coding sequence.

AY664783, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)), an incomplete coding sequence.

AY664784, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)), an incomplete coding sequence.

AY664785, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)), an incomplete coding sequence.

AY664786, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / pigeon / Hong Kong / WF53 / 03 (H9N2)), an incomplete coding sequence.

AY664787, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)), an incomplete coding sequence.

AY664788, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / Guinea fowl / Hong Kong / NT184 / 03 (H9N2), an incomplete coding sequence.

AY664789, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)), an incomplete coding sequence.

AY664790, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)), an incomplete coding sequence.

AY664791, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)), an incomplete coding sequence.

AY800239, the gene for the polymerase base protein 1 (PB1) of influenza A virus (A / chicken / Korea / S1 / 2003 (H9N2)), an incomplete coding sequence.

AY862694, gene PB1 (PB1) of influenza A virus (A / silk chicken / Korea / S3 / 03 (H9N2)), incomplete coding sequence.

AY862695, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S4 / 03 (H9N2)), incomplete coding sequence.

AY862696, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S5 / 03 (H9N2)), incomplete coding sequence.

AY862697, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)), incomplete coding sequence.

AY862698, gene PB1 (PB1) of influenza A virus (A / duck / Korea / S13 / 03 (H9N2)), an incomplete coding sequence.

AY862699, gene PB1 (PB1) of influenza A virus (A / pigeon / Korea / S14 / 03 (H9N2)), incomplete coding sequence.

AY862700, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S15 / 03 (H9N2)), incomplete coding sequence.

AY862701, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S16 / 03 (H9N2)), incomplete coding sequence.

AY862702, gene PB1 (PB1) of influenza A virus (A / chicken / Korea / S18 / 03 (H9N2)), an incomplete coding sequence.

AF156416, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / chicken / Hong Kong / G9 / 97 (H9N2)), an incomplete coding sequence.

AF156417, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / chicken / Hong Kong / G23 / 99 (H9N2)), an incomplete coding sequence.

AF156418, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / pigeon / Hong Kong / Y233 / 97 (H9N2)), an incomplete coding sequence.

AF156419, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / duck / Hong Kong / Y280 / 97 (H9N2)), an incomplete coding sequence.

AF156420, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / duck / Hong Kong / Y439 / 97 (H9N2)), an incomplete coding sequence.

AF156421, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / quail / Hong Kong / G1 / 97 (H9N2)), an incomplete coding sequence.

AF156422, segment 2 gene of the polymerase subunit of PB1 (PB1) of influenza A virus (A / chicken / Hong Kong / 739/94 (H9N2)), an incomplete coding sequence.

AF156423, gene for segment 2 of the polymerase subunit PB1 (PB1) of influenza A virus (A / chicken / Beijin / 1/94 (H9N2)), an incomplete coding sequence.

AF156424, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / quail / Hong Kong / AF157 / 92 (H9N2)), an incomplete coding sequence.

AF156425, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / chicken / Korea / 38349-p96323 / 96 (H9N2)), an incomplete coding sequence.

AF156426, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / chicken / Korea / 25232-96006 / 96 (H9N2)), an incomplete coding sequence.

AF156427, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / plover / Delaware / 9/96 (H9N2)), an incomplete coding sequence.

AF156428, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / quail / Arkansas / 29209-1 / 93 (H9N2)), incomplete coding sequence.

AF156429, segment 2 gene of the polymerase subunit PB1 (PB1) of influenza A virus (A / Turkey / California / 189/66 (H9N2)), an incomplete coding sequence.

AF222632, influenza A virus polymerase 1 (PB1) segment 2 gene (A / quail / Hong Kong / A17 / 99 (H9N2)), incomplete coding sequence.

AF222633, influenza A virus polymerase 1 (PB1) segment 2 gene (A / pigeon / Hong Kong / FY6 / 99 (H9N2)), incomplete coding sequence.

AF222634, influenza A virus polymerase 1 (PB1) segment 2 gene (A / chicken / Hong Kong / NT16 / 99 (H9N2)), incomplete coding sequence.

AF222635, influenza A virus polymerase 1 (PB1) segment 2 gene (A / quail / Hong Kong / SSP10 / 99 (H9N2)), incomplete coding sequence.

AF222636, influenza A virus polymerase 1 (PB1) segment 2 gene (A / pheasant / Hong Kong / SSP11 / 99 (H9N2)), incomplete coding sequence.

AF222637, influenza A virus polymerase 1 (PB1) segment 2 gene (A / chicken / Hong Kong / FY20 / 99 (H9N2)), incomplete coding sequence.

AF222638, influenza A virus polymerase 1 (PB1) segment 2 gene (A / chicken / Hong Kong / KC12 / 99 (H9N2)), incomplete coding sequence.

AF222639, influenza A virus polymerase 1 (PB1) segment 2 gene (A / quail / Hong Kong / NT2899 (H9N2)), incomplete coding sequence.

AF222640, influenza A virus polymerase 1 (PB1) segment 2 gene (A / chicken / Hong Kong / SF2 / 99 (H9N2)), incomplete coding sequence.

AF222641, influenza A virus polymerase 1 (PB1) segment 2 gene (A / silk chicken / Hong Kong / SF44 / 99 (H9N2)), incomplete coding sequence.

The sequences used in the analysis of the main polymerase protein 2 (PB2) of influenza A virus

gi | 49356919 | AY633219 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / mallard / Alberta / 211/98 (H1N1)), an incomplete coding sequence.

gi | 27466107 | AY180748 | gene of the polymerase subunit of PB2 (PB2) of influenza virus strain A / quail / Nanhan / 12-340 / 2000 (H1N1), an incomplete coding sequence.

gi | 45272173 | AY422042 | influenza A virus polymerase subunit (PB2) gene (A / duck / Hokkaido / 95/01 (H2N2)), incomplete coding sequence.

gi | 18091825 | AF213910 | Influenza A virus polymerase PB2 protein segment 1 gene (A / chicken / Italy / 5945/95 (H3N2)), incomplete coding sequence.

gi | 27466133 | AY180761 | gene of the polymerase subunit of PB2 (PB2) of influenza virus strain A / chicken / Nanhan / 3-120 / 2001 (H3N2), an incomplete coding sequence.

gi | 56160002 | AY779267 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)), an incomplete coding sequence.

gi | 56160004 | AY779268 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429704 | AY862719 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S6 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429706 | AY862720 | the influenza A virus PB2 (PB2) gene (A / duck / Korea / S7 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429708 | AY862721 | the influenza A virus PB2 (PB2) gene (A / duck / Korea / S8 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429710 | AY862722 | the influenza A virus PB2 (PB2) gene (A / duck / Korea / S9 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429712 | AY862723 | the influenza A virus PB2 (PB2) gene (A / duck / Korea / S10 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429714 | AY862724 | the influenza A virus PB2 (PB2) gene (A / pigeon / Korea / S11 / 03 (H3N2)), an incomplete coding sequence.

gi | 5805276 | AF144300 | influenza A virus polymerase (PB2) gene (A / goose / Guangdong / 1/96 (H5N1)), full-length coding sequence.

gi | 3335416 | AF046086 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / 220/97 (H5N1)), an incomplete coding sequence.

gi | 60488411 | AF098577 | the influenza A virus PB2 (PB2) protein gene (A / chicken / Hong Kong / 258/97 (H5N1)), an incomplete coding sequence.

gi | 6048843 | AF098578 | influenza A virus PB2 (PB2) protein gene (A / chicken / Hong Kong / y388 / 97 (H5N1)), incomplete coding sequence.

gi | 6048845 | AF098579 | the influenza A virus PB2 (PB2) protein gene (A / chicken / Hong Kong / 728/97 (H5N1)), an incomplete coding sequence.

gi | 6048847 | AF098580 | the influenza A virus PB2 (PB2) protein gene (A / chicken / Hong Kong / 786/97 (H5N1)), an incomplete coding sequence.

gi | 6048849 | AF098581 | the influenza A virus PB2 (PB2) protein gene (A / chicken / Hong Kong / 915/97 (H5N1)), an incomplete coding sequence.

gi | 6048851 | AF098582 | influenza A virus PB2 (PB2) protein gene (A / duck / Hong Kong / p46 / 97 (H5N1)), an incomplete coding sequence.

gi | 6048853 | AF098583 | influenza A virus PB2 (PB2) protein gene (A / duck / Hong Kong / y283 / 97 (H5N1)), incomplete coding sequence.

gi | 6048855 | AF098584 | influenza A virus PB2 (PB2) protein gene (A / goose / Hong Kong / w355 / 97 (H5N1)), incomplete coding sequence.

gi | 14860983 | AY038798 | influenza A virus PB2 (PB2) protein gene (A / goose / Guangdong / 3/1997 (H5N1)), full-length coding sequence.

gi | 47156244 | AY585513 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)), a full-length coding sequence.

gi | 9863884 | AF216717 | influenza A virus polymerase base protein 2 gene (A / environment / Hong Kong / 437-4 / 99 (H5N1)), incomplete coding sequence.

gi | 9863903 | AF216725 | influenza A virus polymerase base protein 2 gene (A / environment / Hong Kong / 437-6 / 99 (H5N1)), incomplete coding sequence.

gi | 9863921 | AF216733 | influenza A virus polymerase base protein 2 gene (A / environment / Hong Kong / 437-8 / 99 (H5N1)), incomplete coding sequence.

gi | 9863939 | AF216741 | influenza A virus polymerase base protein 2 gene (A / environment / Hong Kong / 437-10 / 99 (H5N1)), incomplete coding sequence.

gi | 47156264 | AY585523 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Zheyan / 11/2000 (H5N1)), a full-length coding sequence.

gi | 47156266 | AY585524 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Zheyan / 52/2000 (H5N1)), a full-length coding sequence.

gi | 47156232 | AY585507 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Fujiyan / 19/2000 (H5N1)), a full-length coding sequence.

gi | 47156236 | AY585509 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)), a full-length coding sequence.

gi | 47156238 | AY585510 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)), a full-length coding sequence.

gi | 47156242 | AY585512 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)), a full-length coding sequence.

gi | 19697849 | AY059520 | influenza A virus polymerase (PB2) segment 1 gene (A / goose / Hong Kong / ww26 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697851 | AY059521 | influenza A virus polymerase (PB2) segment 1 gene (A / goose / Hong Kong / ww28 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697853 | AY059522 | influenza A virus polymerase (PB2) segment 1 gene (A / duck / Hong Kong / ww381 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697855 | AY059523 | influenza A virus polymerase (PB2) segment 1 gene (A / duck / Hong Kong / ww461 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697857 | AY059524 | influenza A virus polymerase (PB2) segment 1 gene (A / goose / Hong Kong / ww491 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697859 | AY059525 | influenza A virus polymerase (PB2) segment 1 gene (A / duck / Hong Kong / 2986.1 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697867 | AY059529 | influenza A virus polymerase (PB2) segment 1 gene (A / goose / Hong Kong / 3014.8 / 2000 (H5N1)), incomplete coding sequence.

gi | 18092181 | AF398425 | influenza A virus polymerase (PB2) gene (A / goose / Hong Kong / 385.3 / 2000 (H5N1)), incomplete coding sequence.

gi | 18092183 | AF398426 | influenza A virus polymerase (PB2) gene (A / goose / Hong Kong / 385.5 / 2000 (H5N1)), incomplete coding sequence.

gi | 21359665 | AF468840 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Anyang / AVL-1/2001 (H5N1)), an incomplete coding sequence.

gi | 28849606 | AF509143 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / FY77 / 01 (H5N1)), incomplete coding sequence.

gi | 28849608 | AF509144 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), incomplete coding sequence.

gi | 28849610 | AF509145 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / YU563 / 01 (H5N1)), incomplete coding sequence.

gi | 28849612 | AF509146 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), incomplete coding sequence.

gi | 28849614 | AF509147 | influenza A virus polymerase (PB2) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), incomplete coding sequence.

gi | 28849616 | AF509148 | influenza A virus polymerase (PB2) gene (A / silk chicken / Hong Kong / SF189 / 01 (H5N1)), incomplete coding sequence.

gi | 28849618 | AF509149 | influenza A virus polymerase (PB2) gene (A / quail / Hong Kong / SF203 / 01 (H5N1)), incomplete coding sequence.

gi | 28849620 | AF509150 | influenza A virus polymerase (PB2) gene (A / pigeon / Hong Kong / SF215 / 01 (H5N1)), incomplete coding sequence.

gi | 28849622 | AF509151 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / SF219 / 01 (H5N1)), incomplete coding sequence.

gi | 28849624 | AF509152 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 715.5 / 01 (H5N1)), incomplete coding sequence.

gi | 28849626 | AF509153 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 751.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849628 | AF509154 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 822.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849630 | AF509155 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 829.2 / 01 (H5N1)), incomplete coding sequence.

gi | 28849632 | AF509156 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 830.2 / 01 (H5N1)), incomplete coding sequence.

gi | 28849634 | AF509157 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 858.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28849636 | AF509158 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 866.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28849638 | AF509159 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 867.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849640 | AF509160 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 879.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849642 | AF509161 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 873.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28849644 | AF509162 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 876.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849646 | AF509163 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 891.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849648 | AF509164 | influenza A virus polymerase (PB2) gene (A / chicken / Hong Kong / 893.2 / 01 (H5N1)), incomplete coding sequence.

gi | 28849650 | AF509165 | influenza A virus polymerase (PB2) gene (A / goose / Hong Kong / 76.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849652 | AF509166 | influenza A virus polymerase (PB2) gene (A / goose / Hong Kong / ww100 / 01 (H5N1)), incomplete coding sequence.

gi | 28849654 | AF509167 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 573.4 / 01 (H5N1)), incomplete coding sequence.

gi | 28849656 | AF509168 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 646.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28823262 | AY221584 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / NT873.3 / 01-MB (H5N1)), an incomplete coding sequence.

gi | 28823443 | AY221585 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / NT873.3 / 01 (H5N1)), an incomplete coding sequence.

gi | 28823612 | AY221586 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / FY150 / 01-MB (H5N1)), an incomplete coding sequence.

gi | 28823783 | AY221587 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / FY150 / 01 (H5N1)), an incomplete coding sequence.

gi | 28823961 | AY221588 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / pheasant / Hong Kong / FY155 / 01-MB (H5N1)), an incomplete coding sequence.

gi | 28824143 | AY221589 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), an incomplete coding sequence.

gi | 28824334 | AY221590 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / YU822.2 / 01-MB (H5N1)), an incomplete coding sequence.

gi | 28824502 | AY221591 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / YU822.2 / 01 (H5N1)), an incomplete coding sequence.

gi | 28824684 | AY221592 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / YU562 / 01 (H5N1)), an incomplete coding sequence.

gi | 47156230 | AY585506 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Fuyang / 17/2001 (H5N1)), a full-length coding sequence.

gi | 47156234 | AY585508 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)), a full-length coding sequence.

gi | 47156246 | AY585514 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)), a full-length coding sequence.

gi | 47156248 | AY585515 | mRNA polymerase 2 (PB2) of influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)), full-length coding sequence.

gi | 47156250 | AY585516 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)), a full-length coding sequence.

gi | 47156254 | AY585518 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Shanghai / 08/2001 (H5N1)), a full-length coding sequence.

gi | 47156256 | AY585519 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Shanghai / 13/2001 (H5N1)), a full-length coding sequence.

gi | 47156262 | AY585522 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Shanghai / 38/2001 (H5N1)), a full-length coding sequence.

gi | 47156258 | AY585520 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Shanghai / 35/2002 (H5N1)), a full-length coding sequence.

gi | 47156260 | AY585521 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Shanghai / 37/2002 (H5N1)), a full-length coding sequence.

gi | 47156252 | AY585517 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)), a full-length coding sequence.

gi | 47156240 | AY585511 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)), a full-length coding sequence.

gi | 47834791 | AY576382 | influenza A virus polymerase (PB2) gene (A / Gs / HK / 739.2 / 02 (H5N1)), incomplete coding sequence.

gi | 47834793 | AY576383 | influenza A virus polymerase (PB2) gene (A / Eg / HK / 757.3 / 02 (H5N1)), incomplete coding sequence.

gi | 47834795 | AY576384 | influenza A virus polymerase (PB2) gene (A / G.H / HK / 793.1 / 02 (H5N1)), incomplete coding sequence.

gi | 47834797 | AY576385 | influenza A virus polymerase (PB2) gene (A / duck / HK / 821/02 (H5N1)), incomplete coding sequence.

gi | 47834799 | AY576386 | influenza A virus polymerase (PB2) gene (A / chicken / HK / 31.4 / 02 (H5N1)), incomplete coding sequence.

gi | 47834801 | AY576387 | influenza A virus polymerase (PB2) gene (A / Ck / HK / 61.9 / 02 (H5N1)), incomplete coding sequence.

gi | 47834803 | AY576388 | influenza A virus polymerase (PB2) gene (A / Ck / HK / YU777 / 02 (H5N1)), incomplete coding sequence.

gi | 47834805 | AY576389 | influenza A virus polymerase (PB2) gene (A / Ck / HK / 96.1 / 02 (H5N1)), incomplete coding sequence.

gi | 47834807 | AY576390 | influenza A virus polymerase (PB2) gene (A / Ck / HK / 409.1 / 02 (H5N1)), incomplete coding sequence.

gi | 47834809 | AY576391 | influenza A virus polymerase (PB2) gene (A / Ph / HK / sv674.15 / 02 (H5N1)), incomplete coding sequence.

gi | 47156226 | AY585504 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Fuyang / 01/2002 (H5N1)), a full-length coding sequence.

gi | 47156228 | AY585505 | mRNA of the polymerase base protein 2 (PB2) of influenza A virus (A / duck / Fuyang / 13/2002 (H5N1)), a full-length coding sequence.

gi | 50296597 | AY651744 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / gray heron / HK / 861.1 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296599 | AY651745 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / feral pigeon / HK / 862.7 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296601 | AY651746 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / tree sparrow / HK / 864/2002 (H5N1)), an incomplete coding sequence.

gi | 50296603 | AY651747 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)), an incomplete coding sequence.

gi | 56548879 | AY676021 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / duck / Hong Kong / 821/02 (H5N1)), a full-length coding sequence.

gi | 50296569 | AY651730 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Gf / HK / 38/2002 (H5N1)), an incomplete coding sequence.

gi | 50296571 | AY651731 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296573 | AY651732 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296575 | AY651733 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296577 | AY651734 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296579 | AY651735 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296581 | AY651736 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)), an incomplete coding sequence.

gi | 50296583 | AY651737 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296585 | AY651738 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296587 | AY651739 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296589 | AY651740 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296591 | AY651741 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296593 | AY651742 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296595 | AY651743 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / black-headed gull / HK / 12.1 / 2003 (H5N1)), an incomplete coding sequence.

gi | 50296607 | AY651749 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / HN / 5806/2003 (H5N1)), an incomplete coding sequence.

gi | 50296609 | AY651750 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / ST / 4003/2003 (H5N1)), an incomplete coding sequence.

gi | 50296611 | AY651751 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / ST / 4231/2003 (H5N1)), an incomplete coding sequence.

gi | 50296613 | AY651752 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / YN / 6255/2003 (H5N1)), an incomplete coding sequence.

gi | 50296615 | AY651753 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / YN / 6445/2003 (H5N1)), an incomplete coding sequence.

gi | 50296529 | AY651710 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)), an incomplete coding sequence.

gi | 56548881 | AY676022 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / white egret / Hong Kong / 757.2 / 03 (H5N1)), a full-length coding sequence.

gi | 56548883 | AY676023 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / ES / 03 (H5N1)), a full-length coding sequence.

gi | 56548885 | AY676024 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / duck / Korea / ESD1 / 03 (H5N1)), a full-length coding sequence.

gi | 50296519 | AY651705 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)), a full-length coding sequence.

gi | 50296523 | AY651707 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)), a full-length coding sequence.

gi | 41207501 | AY518367 | gene of the polymerase subunit of PB2 (PB2) of influenza A virus (A / duck / China / E319-2 / 03 (H5N1)), a full-length coding sequence.

gi | 45359369 | AY550147 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Patom Highlands / Thailand / CU-K2 / 04 (H5N1)), an incomplete coding sequence.

gi | 50296525 | AY651708 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)), an incomplete coding sequence.

gi | 50296527 | AY651709 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)), an incomplete coding sequence.

gi | 50296521 | AY651706 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)), a full-length coding sequence.

gi | 51094103 | AY590581 | gene for the polymerase base protein 2 (PBP2) of influenza A virus (A / chicken / Patom Highlands / Thailand / CU-K2 / 2004 (H5N1)), an incomplete coding sequence.

gi | 47716766 | AY609309 | Influenza A virus segment 1 (A / chicken / Guangdong / 174/04 (H5N1)), full length sequence.

gi | 58531082 | AB166859 | the gene for the polymerase base protein 2 of the PB2 virus of influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)), a full-length coding sequence.

gi | 58531114 | AB188813 | gene for the polymerase base protein 2 of the PB2 virus of influenza A virus (A / chicken / Oita / 8/2004 (H5N1)), a full-length coding sequence.

gi | 50956621 | AY684703 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)), a full-length coding sequence.

gi | 57915957 | AY737286 | Influenza A virus segment 1 (A / chicken / Guangdong / 191/04 (H5N1)), full length sequence.

gi | 57916006 | AY737293 | Influenza A virus segment 1 (A / chicken / Guangdong / 178/04 (H5N1)), full length sequence.

gi | 57916060 | AY737301 | Influenza A virus segment 1 (A / duck / Guangdong / 173/04 (H5N1)), full length sequence.

gi | 55233237 | AY770084 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)), a full-length coding sequence.

gi | 54873461 | AY770993 | influenza A virus polymerase base protein 2 gene (A / chicken / Autthaya / Thailand / CU-23/04 (H5N1)), incomplete coding sequence.

gi | 58618421 | AY818127 | influenza A virus polymerase protein PB2 gene (A / chicken / Vietnam / C58 / 04 (H5N1)), full-length coding sequence.

gi | 58618423 | AY818128 | gene of the influenza A virus polymerase protein PB2 (A / quail / Vietnam / 36/04 (H5N1)), full-length coding sequence.

gi | 58374183 | AY856861 | Influenza A virus segment 1 (A / duck / Shandu / 093/2004 (H5N1)), full length sequence.

gi | 58531132 | AB188821 | gene for the polymerase base protein 2 of the PB2 virus of influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)), a full-length coding sequence.

gi | 58531150 | AB189050 | gene for the polymerase base protein 2 of the PB2 virus of influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)), a full-length coding sequence.

gi | 58531168 | AB189058 | gene for the polymerase base protein 2 of the PB2 virus of influenza A virus (A / raven / Osaka / 102/2004 (H5N1)), a full-length coding sequence.

gi | 50296605 | AY651748 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)), a full-length coding sequence.

gi | 50296531 | AY651711 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)), an incomplete coding sequence.

gi | 50296533 | AY651712 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)), an incomplete coding sequence.

gi | 50296535 | AY651713 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)), a full-length coding sequence.

gi | 50296537 | AY651714 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)), a full-length coding sequence.

gi | 50296539 | AY651715 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / avian / Thailand / 3.1 / 2004 (H5N1)), a full-length coding sequence.

gi | 50296541 | AY651716 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)), a full-length coding sequence.

gi | 50296543 | AY651717 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)), an incomplete coding sequence.

gi | 50296553 | AY651722 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)), a full-length coding sequence.

gi | 50296555 | AY651723 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)), a full-length coding sequence.

gi | 50296557 | AY651724 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)), a full-length coding sequence.

gi | 50296559 | AY651725 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)), a full-length coding sequence.

gi | 50296561 | AY651726 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)), a full-length coding sequence.

gi | 50296563 | AY651727 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)), a full-length coding sequence.

gi | 50296565 | AY651728 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)), a full-length coding sequence.

gi | 50296567 | AY651729 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)), a full-length coding sequence.

gi | 50296617 | AY651754 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / YN / 374/2004 (H5N1)), an incomplete coding sequence.

gi | 50296619 | AY651755 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ck / YN / 115/2004 (H5N1)), an incomplete coding sequence.

gi | 50296621 | AY651756 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Ph / ST / 44/2004 (H5N1)), an incomplete coding sequence.

gi | 50296623 | AY651757 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / HN / 303/2004 (H5N1)), an incomplete coding sequence.

gi | 50296625 | AY651758 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / Dk / HN / 101/2004 (H5N1)), an incomplete coding sequence.

gi | 50365712 | AY653193 | Influenza A virus segment 1 (A / chicken / Jilin / 9/2004 (H5N1)), full length sequence.

gi | 47680940 | AY586445 | influenza A virus PB2 gene (A / Mallard / Italy / 43/01 (H7N3)), incomplete coding sequence.

gi | 47680930 | AY586440 | influenza A virus PB2 gene (A / Mallard / Italy / 33/01 (H7N3)), incomplete coding sequence.

gi | 47680932 | AY586441 | influenza A virus PB2 gene (A / turkey / Italy / 220158/2002 (H7N3)), incomplete coding sequence.

gi | 45124743 | AJ627485 | influenza A virus RNA polymerase PB2 gene (A / turkey / Italy / 214845/2002 (H7N3)), genomic RNA.

gi | 45124767 | AJ627496 | influenza A virus RNA polymerase PB2 gene (A / turkey / Italy / 220158/2002 (H7N3)), genomic RNA.

gi | 34597782 | AY303665 | the gene for the polymerase base protein 2 of influenza A virus (A / chicken / Chile / 176822/02 (H7N3)), an incomplete coding sequence.

gi | 34597784 | AY303666 | the gene for the polymerase base protein 2 of influenza A virus (A / chicken / Chile / 4957/02 (H7N3)), an incomplete coding sequence.

gi | 47680928 | AY586439 | influenza A virus PB2 gene (A / turkey / Italy / 214845/02 (H7N3)), incomplete coding sequence.

gi | 47834374 | AYS16766 | gene of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / British Columbia / 04 (H7N3)), a full-length coding sequence.

gi | 50542651 | AY646085 | influenza A virus polymerase base protein 2 gene (A / chicken / British Columbia / GSC_man_B / 04 (H7N3)), full-length coding sequence.

gi | 50083053 | AY648294 | gene for the polymerase subunit of PB2 (PB2) of influenza A virus (A / GSC_ chicken_B / British Columbia / 04 (H7N3)), a full-length coding sequence.

gi | 50059194 | AY650276 | influenza A virus polymerase subunit gene PB2 (PB2) gene (A / GSC_ chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

gi | 60700 | X58691 | gene of the cap-binding protein PB2 of influenza A virus (A / FPV / Dobson / 27 (H7N7)), genomic RNA.

gi | 325001 | M38291 | gene (segment 3) of the polymerase base protein 2 (PB2) of the influenza A / FPV / Weybridge virus, a full-length coding sequence.

gi | 9988661 | AF268120 | influenza A virus polymerase PB2 gene (A / Icelandic sandpiper / Delaware / 259/94 (H7N7)), incomplete coding sequence.

gi | 40732893 | AJ620347 | gene of the RNA polymerase protein PB2 of influenza A virus (A / chicken / Germany / R28 / 03 (H7N7)) A / chicken / Germany / R28 / 03 (H7N7)), genomic RNA.

gi | 37813157 | AY342410 | gene polymerase protein 2 (A / Netherlands / 124/03 (H7N7)), an incomplete coding sequence.

gi | 37813159 | AY342411 | influenza A virus polymerase protein 2 gene (A / Netherlands / 126/03 (H7N7)), incomplete coding sequence.

gi | 37813161 | AY342412 | influenza A virus polymerase protein 2 gene (A / Netherlands / 127/03 (H7N7)), incomplete coding sequence.

gi | 37813163 | AY342413 | influenza A virus polymerase protein 2 gene (A / Netherlands / 219/03 (H7N7)), incomplete coding sequence.

gi | 37813165 | AY342414 | influenza A virus polymerase protein 2 gene (A / chicken / Netherlands / 1/03 (H7N7)), incomplete coding sequence.

gi | 5732354 | AF156443 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / turkey / California / 189/66 (H9N2)), an incomplete coding sequence.

gi | 31339587 | AF523469 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 86/76 (H9N2)), incomplete coding sequence.

gi | 31339583 | AF523467 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 366/78 (H9N2)), incomplete coding sequence.

gi | 31339605 | AF523478 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 289/78 (H9N2)), incomplete coding sequence.

gi | 31339585 | AF523468 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 552/79 (H9N2)), incomplete coding sequence.

gi | 31339589 | AP523470 | influenza A virus polymerase (PB2) gene (A / duck / Hong Kong / 610/79 (H9N2)), incomplete coding sequence.

gi | 49356935 | AY633283 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / mallard / Alberta / 321/88 (H9N2)), an incomplete coding sequence.

gi | 49356939 | AY633299 | gene for polymerase base protein 2 (PB2) (PB2) (PB2) of influenza A virus (A / mallard / Alberta / 11/91 (H9N2)), incomplete coding sequence.

gi | 49356907 | AY633171 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / mallard / Alberta / 17/91 (H9N2)), an incomplete coding sequence.

gi | 5732342 | AF156437 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / quail / Hong Kong / | AF157 / 92 (H9N2)), an incomplete coding sequence.

gi | 5732352 | AF156442 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / quail / Arkansas / 29209-1 / 93 (H9N2)), an incomplete coding sequence.

gi | 5732340 | AF156436 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / Hong Kong / 739/94 (H9N2)), an incomplete coding sequence.

gi | 5732344 | AF156438 | gene for segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / Beijin / 1/94 (H9N2)), an incomplete coding sequence.

gi | 22759060 | AF536679 | influenza A virus PB2 gene (A / chicken / Beijin / 1/95 (H9N2)), incomplete coding sequence.

gi | 33318110 | AF508640 | gene of segment 1 polymerase PB2 (PB2) of influenza A virus (A / ostrich / South Africa / 9508103/95 (H9N2)), a full-length coding sequence.

gi | 33318118 | AF508644 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / duck / Germany / 113/95 (H9N2)), an incomplete coding sequence.

gi | 33318144 | AF508657 | gene of segment 1 polymerase PB2 (PB2) of influenza A virus (A / chicken / Shandu / 6/96 (H9N2)), an incomplete coding sequence.

gi | 33318152 | AF508661 | the gene of segment 1 polymerase PB2 (PB2) of influenza A virus (A / quail / Shanghai / 8/96 (H9N2)), an incomplete coding sequence.

gi | 5732346 | AF156439 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / Korea / 38349-p96323 / 96 (H9N2)), an incomplete coding sequence.

gi | 5732348 | AF156440 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / Korea / 25232-96006/96 (H9N2)), an incomplete coding sequence.

gi | 5732350 | AF156441 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / plover / Delaware / 9/96 (H9N2)), an incomplete coding sequence.

gi | 22759068 | AF536683 | influenza A virus PB2 gene (A / chicken / Hebei / 1/96 (H9N2)), incomplete coding sequence.

gi | 5732328 | AF156430 | gene for segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / Hong Kong / G9 / 97 (H9N2)), a full-length coding sequence.

gi | 5732330 | AF156431 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / chicken / Hong Kong / G23 / 97 (H9N2)), an incomplete coding sequence.

gi | 5732332 | AF156432 | gene for segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / pigeon / Hong Kong / Y233 / 97 (H9N2)), an incomplete coding sequence.

gi | 5732334 | AF156433 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / duck / Hong Kong / Y280 / 97 (H9N2)), an incomplete coding sequence.

gi | 5732336 | AF156434 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / duck / Hong Kong / Y439 / 97 (H9N2)), an incomplete coding sequence.

gi | 5732338 | AF156435 | gene of segment 1 of the polymerase subunit of PB2 (PB2) of influenza A virus (A / quail / Hong Kong / G1 / 97 (H9N2)), an incomplete coding sequence.

gi | 33318148 | AF508659 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / chicken / Shenzhen / 9/97 (H9N2)), an incomplete coding sequence.

gi | 33318150 | AF508660 | gene of segment 1 polymerase PB2 (PB2) of influenza A virus (A / duck / Nanyang / 1/97 (H9N2)), an incomplete coding sequence.

gi | 33318124 | AF508647 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / pheasant / Ireland / PV18 / 97 (H9N2)), an incomplete coding sequence.

gi | 13383266 | AB049153 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / parrot / Chiba / 1/97 (H9N2)), a full-length coding sequence.

gi | 33318132 | AF508651 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / chicken / Guangdong / 11/97 (H9N2)), an incomplete coding sequence.

gi | 33318136 | AF508653 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / chicken / Heylonyan / 10/97 (H9N2)), an incomplete coding sequence.

gi | 22759062 | AF536680 | influenza A virus PB2 gene (A / chicken / Beijin / 2/97 (H9N2)), incomplete coding sequence.

gi | 33318142 | AF508656 | the gene for segment 1 of the polymerase PB2 (PB2) of influenza A virus (A / chicken / Xihuan / 5/97 (H9N2)), an incomplete coding sequence.

gi | 22759066 | AF536682 | influenza A virus PB2 gene (A / chicken / Guangdong / 97 (H9N2)), incomplete coding sequence.

gi | 22759078 | AF536688 | influenza A virus PB2 gene (A / chicken / Shandu / 98 (H9N2)), incomplete coding sequence.

gi | 33318116 | AF508643 | gene of segment 1 polymerase PB2 (PB2) of influenza A virus (A / chicken / Germany / R45 / 98 (H9N2)), an incomplete coding sequence.

gi | 33318134 | AF508652 | the gene for segment 1 polymerase PB2 (PB2) of influenza A virus (A / chicken / Hebei / 4/98 (H9N2)), an incomplete coding sequence.

gi | 33318128 | AF508649 | gene of segment 1 of polymerase PB2 (PB2) of influenza A virus (A / chicken / Beijin / 8/98 (H9N2)), a full-sized coding sequence.

gi | 13383268 | AB049154 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / parrot / Narita / 92A / 98 (H9N2)), a full-length coding sequence.

gi | 22759070 | AF536684 | influenza A virus PB2 gene (A / chicken / Hebei / 2/98 (H9N2)), incomplete coding sequence.

gi | 22759072 | AF536685 | influenza A virus PB2 gene (A / chicken / Hebei / 3/98 (H9N2)), incomplete coding sequence.

gi | 22759074 | AF536686 | influenza A virus PB2 gene (A / chicken / Henan / 98 (H9N2)), incomplete coding sequence.

gi | 30025722 | AY253750 | influenza A virus RNA polymerase (PB2) gene (A / chicken / Shanghai / F / 98 (H9N2)), full-length coding sequence.

gi | 12060631 | AF222622 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / quail / Hong Kong / A17 / 99 (H9N2)), incomplete coding sequence.

gi | 12060633 | AF222623 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / pigeon / Hong Kong / FY6 / 99 (H9N2)), incomplete coding sequence.

gi | 12060635 | AF222624 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / chicken / Hong Kong / NT16 / 99 (H9N2)), incomplete coding sequence.

gi | 12060637 | AF222625 | influenza A virus polymerase 2 (PB2) segment 1 gene (A / quail / Hong Kong / SSP10 / 99 (H9N2)), incomplete coding sequence.

gi | 12060639 | AF222626 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / pheasant / Hong Kong / SSP11 / 99 (H9N2)), incomplete coding sequence.

gi | 12060641 | AF222627 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / chicken / Hong Kong / FY20 / 99 (H9N2)), incomplete coding sequence.

gi | 12060643 | AF222628 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / chicken / Hong Kong / KC12 / 99 (H9N2)), incomplete coding sequence.

gi | 12060645 | AF222629 | influenza A virus polymerase 2 (PB2) segment 1 gene (A / quail / Hong Kong / NT28 / 99 (H9N2)), incomplete coding sequence.

gi | 12060647 | AF222630 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / chicken / Hong Kong / SF2 / 99 (H9N2)), incomplete coding sequence.

gi | 12060649 | AF222631 | influenza A virus polymerase 2 (PB2) segment 1 gene (A / silk chicken / Hong Kong / SF44 / 99 (H9N2)), incomplete coding sequence.

gi | 22759076 | AF536687 | influenza A virus PB2 gene (A / chicken / Liaoning / 99 (H9N2)), incomplete coding sequence.

gi | 33318112 | AF508641 | gene for segment 1 of polymerase 2 (PB2) of influenza A virus (A / chicken / Pakistan / 4/99 (H9N2)), a full-length coding sequence.

gi | 33318114 | AF508642 | Influenza A virus polymerase 2 (PB2) segment 1 gene (A / chicken / Pakistan / 5/99 (H9N2)), full-length coding sequence.

gi | 33318126 | AF508648 | gene of segment 1 of polymerase 2 (PB2) of influenza A virus (A / chicken / Korea / 99029/99 (H9N2)), an incomplete coding sequence.

gi | 33318120 | AF508645 | gene of segment 1 of polymerase 2 (PB2) of influenza A virus (A / chicken / Iran / 11T / 99 (H9N2)), a full-length coding sequence.

gi | 33318122 | AF508646 | gene of segment 1 of polymerase 2 (PB2) of influenza A virus (A / chicken / Saudi Arabia / 532/99 (H9N2)), an incomplete coding sequence.

gi | 33318140 | AF508655 | gene of segment 1 of polymerase 2 (PB2) of influenza A virus (A / chicken / Ningsia / 5/99 (H9N2)), an incomplete coding sequence.

gi | 33318146 | AF508658 | gene of segment 1 of polymerase 2 (PB2) of influenza A virus (A / chicken / Shiyazhuan / 2/99 (H9N2)), an incomplete coding sequence.

gi | 12038893 | AJ291395 | influenza A virus polymerase PB2 gene (A / chicken / Pakistan / 2/99 (H9N2)), genomic RNA.

gi | 22759064 | AF536681 | influenza A virus PB2 gene (A / chicken / Beijin / 3/99 (H9N2)), incomplete coding sequence.

gi | 31339607 | AF523479 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 1881/00 (H9N2)), incomplete coding sequence.

gi | 31339601 | AF523476 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 830/00 (H9N2)), incomplete coding sequence.

gi | 31339603 | AF523477 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 1796/00 (H9N2)), incomplete coding sequence.

gi | 18496117 AJ427861 | incomplete gene pb2 polymerase protein PB2 of influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)), genomic RNA.

gi | 27466041 | AY180715 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / wild duck / Nanhan / 2-0480 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466043 | AY180716 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / pigeon / Nanhan / 2-0461 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466045 | AY180717 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / duck / Nanhan / 1-0070 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466055 | AY180722 | the gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / duck / Nanhan / 10-389 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466057 | AY180723 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / pigeon / Nanhan / 7-058 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466067 | AY180728 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / quail / Nanhan / 2-0460 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466085 | AY180737 | gene of the polymerase subunit of the PB2 (PB2) virus of influenza A strain A / pigeon / Nanhan / 11-145 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466087 | AY180738 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / duck / Nanhan / 11-197 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466091 | AY180740 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / duck / Nanhan / 11-290 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466093 | AY180741 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / duck / Nanhan / 11-392 / 2000 (H9N2), an incomplete coding sequence.

gi | 31339575 | AF523463 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 2134/00 (H9N2)), incomplete coding sequence.

gi | 31339579 | AF523465 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 1043/00 (H9N2)), incomplete coding sequence.

gi | 31339581 | AF523466 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 1042/00 (H9N2)), incomplete coding sequence.

gi | 31339593 | AF523472 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 2102/00 (H9N2)), incomplete coding sequence.

gi | 31339595 | AF523473 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 2144/00 (H9N2)), incomplete coding sequence.

gi | 31339597 | AF523474 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 2143/00 (H9N2)), incomplete coding sequence.

gi | 33318138 | AF508654 | influenza A virus polymerase (PB2) segment 1 gene (A / chicken / Henan / 62/00 (H9N2)), incomplete coding sequence.

gi | 33318130 | AF508650 | influenza A virus polymerase (PB2) segment 1 gene (A / chicken / Guangdong / 10/00 (H9N2)), incomplete coding sequence.

gi | 27466121 | AY180755 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / duck / Nanhan / 7-092 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466141 | AY180765 | gene of the polymerase subunit of PB2 (PB2) of influenza A virus strain A / chicken / Nanhan / 4-010 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466157 | AY180773 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / quail / Nanhan / 4-040 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466159 | AY180774 | gene of the polymerase subunit of PB2 (PB2) of influenza A strain A strain / chicken / Nanhan / 1-0016 / 2000 (H9N2), an incomplete coding sequence.

gi | 55469788 | AY768575 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU0028 / 00 (H9N2)), an incomplete coding sequence.

gi | 55469790 | AY768576 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU0037 / 00 (H9N2)), an incomplete coding sequence.

gi | 55469792 | AY768577 | the gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU0073 / 00 (H9N2)), an incomplete coding sequence.

gi | 55469794 | AY768578 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU0091 / 00 (H9N2)), an incomplete coding sequence.

gi | 55469796 | AY768579 | the gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU0140 / 00 (H9N2)), an incomplete coding sequence.

gi | 55469798 | AY768580 | gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU0146 / 00 (H9N2)), an incomplete coding sequence.

gi | 55469800 | AY768581 | the gene for the polymerase base subunit 2 (PB2) of influenza A virus (A / chicken / Korea / SNU1035C / 00 (H9N2)), an incomplete coding sequence.

gi | 27466143 | AY180766 | gene of the polymerase subunit of the PB2 (PB2) virus of influenza A strain A / chicken / Nanhan / 4-301 / 2001 (H9N2), an incomplete coding sequence.

gi | 31339599 | AF523475 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 2088/01 (H9N2)), incomplete coding sequence.

gi | 31339591 | AF523471 | influenza A virus polymerase (PB2) gene (A / duck / Shantu / 1605/01 (H9N2)), incomplete coding sequence.

gi | 31339577 | AF523464 | influenza A virus polymerase (PB2) gene (A / wild duck / Shantu / 4808/01 (H9N2)), incomplete coding sequence.

gi | 27466097 | AY180743 | gene of the polymerase subunit of PB2 (PB2) of influenza A virus strain A / chicken / Nanhan / 4-361 / 2001 (H9N2), an incomplete coding sequence.

gi | 54398631 | AY664792 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398633 | AY664793 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398635 | AY664794 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398637 | AY664795 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)), incomplete sequence.

gi | 54398638 | AY664796 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)), incomplete sequence.

gi | 54398639 | AY664797 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)), incomplete sequence.

gi | 54398640 | AY664798 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / guinea fowl / Hong Kong / NT101 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398642 | AY664799 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2), an incomplete coding sequence.

gi | 54398644 | AY664800 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / SF1 / 03 (H9N2)), incomplete sequence.

gi | 54398645 | AY664801 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)), incomplete sequence.

gi | 54398646 | AY664802 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398648 | AY664803 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)), incomplete sequence.

gi | 54398649 | AY664804 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / pigeon / Hong Kong / WF53 / 03 (H9N2)), incomplete sequence.

gi | 54398650 | AY664805 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)), incomplete sequence.

gi | 54398651 | AY664806 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / Guinea fowl / Hong Kong / NT184 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398653 | AY664807 | gene of non-functional polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)), incomplete sequence.

gi | 54398654 | AY664808 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398656 | AY664809 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / SSP418 / 03 (H9N2)), an incomplete coding sequence.

gi | 54398658 | AY664810 | the gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)), an incomplete coding sequence.

gi | 55793686 | AY800240 | gene for the polymerase base protein 2 (PB2) of influenza A virus (A / chicken / Korea / S1 / 2003 (H9N2)), an incomplete coding sequence.

gi | 58429686 | AY862710 | the influenza A virus PB2 (PB2) gene (A / silk chicken / Korea / S3 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429688 | AY862711 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S4 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429690 | AY862712 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S5 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429692 | AY862713 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S12 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429694 | AY862714 | the influenza A virus PB2 (PB2) gene (A / duck / Korea / S13 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429696 | AY862715 | the influenza A virus PB2 (PB2) gene (A / pigeon / Korea / S14 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429698 | AY862716 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S15 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429700 | AY862717 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S16 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429702 | AY862718 | the influenza A virus PB2 (PB2) gene (A / chicken / Korea / S18 / 03 (H9N2)), an incomplete coding sequence.

The sequences used in the analysis of the polymerase acid protein of influenza A virus (PA)

gi | 27465935 | AY180662 | gene of the polymerase subunit PA (PA) of influenza A virus of strain A / quail / Nanhan / 12-340 / 2000 (H1N1), an incomplete coding sequence.

gi | 49357063 | AY633217 | influenza A virus polymerase protein A (PA) gene (A / mallard / Alberta / 211/98 (H1N1)), incomplete coding sequence.

gi | 5918195 | AJ243994 | incomplete mRNA of influenza A virus RA protein (strain A / mallard / New York / 6750/78).

gi | 45272157 | AY422034 | influenza A virus PA (PA) protein gene (A / duck / Hokkaido / 95/01 (H2N2)), incomplete coding sequence.

gi | 27465965 | AY180677 | the gene of the polymerase subunit PA (PA) of influenza A virus strain A / chicken / Nanhan / 3-120 / 2001 (H3N2), an incomplete coding sequence.

gi | 56159994 | AY779263 | influenza A virus polymerase acid protein PA (PA) gene (A / turkey / North Carolina / 12344/03 (H3N2)), incomplete coding sequence.

gi | 56159996 | AY779264 | influenza A virus polymerase acid protein PA (PA) gene (A / turkey / Minnesota / 764-2 / 03 (H3N2)), incomplete coding sequence.

gi | 58429736 | AY862687 | influenza A virus PA (PA) gene (A / chicken / Korea / S6 / 03 (H3N2)), incomplete coding sequence.

gi | 58429738 | AY862688 | the influenza A virus PA (PA) gene (A / duck / Korea / S7 / 03 (H3N2)), an incomplete coding sequence.

gi | 58429740 | AY862689 | influenza A virus PA (PA) gene (A / duck / Korea / S8 / 03 (H3N2)), incomplete coding sequence.

gi | 58429742 | AY862690 | influenza A virus PA (PA) gene (A / duck / Korea / S9 / 03 (H3N2)), incomplete coding sequence.

gi | 58429744 | AY862691 | influenza A virus PA (PA) gene (A / duck / Korea / S10 / 03 (H3N2)), incomplete coding sequence.

gi | 58429746 | AY862692 | influenza A virus PA (PA) gene (A / pigeon / Korea / S11 / 03 (H3N2)), incomplete coding sequence.

gi | 18091833 | AF213914 | gene of segment 3 of the polymerase protein RA of influenza A virus A (A / chicken / Italy / 5945/95 (H3N2)), an incomplete coding sequence.

gi | 58531086 | AB166861 | influenza A virus polymerase acid protein RA gene (A / chicken / Yamaguchi / 7/2004 (H5N1)), full-length coding sequence.

gi | 58531118 | AB188815 | influenza A virus polymerase acid protein RA gene (A / chicken / Oita / 8/2004 (H5N1)), full-length coding sequence.

gi | 9863935 | AF216739 | influenza A virus polymerase acid protein gene (A / environment / Hong Kong / 437-10 / 99 (H5N1)), full-length coding sequence.

gi | 14165201 | AF380163 | influenza A virus polymerase (RA) segment 3 gene (A / goose / Guangdong / 3/97 (H5N1)), full-length coding sequence.

gi | 18092185 | AF398427 | influenza A virus polymerase (RA) gene (A / goose / Hong Kong / 385.3 / 2000 (H5N1)), incomplete coding sequence.

gi | 18092187 | AF398428 | influenza A virus polymerase (RA) gene (A / goose / Hong Kong / 385.5 / 2000 (H5N1)), incomplete coding sequence.

gi | 21359667 | AF468841 | influenza A virus polymerase acid protein (PA) gene (A / duck / Anyang / AVL-1/2001 (H5N1)), incomplete coding sequence.

gi | 28849710 | AF509195 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / FY77 / 01 (H5N1)), incomplete coding sequence.

gi | 28849712 | AF509196 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), incomplete coding sequence.

gi | 28849714 | AF509197 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / YU563 / 01 (H5N1)), full-length coding sequence.

gi | 28849716 | AF509198 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), incomplete coding sequence.

gi | 28849718 | AF509199 | influenza A virus polymerase (RA) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), incomplete coding sequence.

gi | 28849720 | AF509200 | influenza A virus polymerase (RA) gene (A / silk chicken / Hong Kong / SF189 / 01 (H5N1)), incomplete coding sequence.

gi | 28849722 | AF509201 | influenza A virus polymerase (RA) gene (A / quail / Hong Kong / SF203 / 01 (H5N1)), incomplete coding sequence.

gi | 28849724 | AF509202 | influenza A virus polymerase (RA) gene (A / pigeon / Hong Kong / SF215 / 01 (H5N1)), incomplete coding sequence.

gi | 28849726 | AF509203 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / SF219 / 01 (H5N1)), incomplete coding sequence.

gi | 28849728 | AF509204 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 715.5 / 01 (H5N1)), incomplete coding sequence.

gi | 28849730 | AF509205 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 751.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849732 | AF509206 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 822.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849734 | AF509207 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 829.2 / 01 (H5N1)), incomplete coding sequence.

gi | 28849736 | AF509208 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 830.2 / 01 (H5N1)), incomplete coding sequence.

gi | 28849738 | AF509209 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 858.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28849740 | AF509210 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 866.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28849742 | AF509211 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 867.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849744 | AF509212 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 879.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849746 | AF509213 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 873.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28849748 | AF509214 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 876.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849750 | AF509215 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 891.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849752] | AF509216 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / 893.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849754 | AF509217 | influenza A virus polymerase (RA) gene (A / goose / Hong Kong / 76.1 / 01 (H5N1)), incomplete coding sequence.

gi | 28849756 | AF509218 | influenza A virus polymerase (RA) gene (A / goose / Hong Kong / ww100 / 01 (H5N1)), incomplete coding sequence.

gi | 28849758 | AF509219) | influenza A virus polymerase (RA) gene (A / duck / Hong Kong / 573.4 / 01 (H5N1)), incomplete coding sequence.

gi | 28849760 | AF509220 | influenza A virus polymerase (RA) gene (A / duck / Hong Kong / 646.3 / 01 (H5N1)), incomplete coding sequence.

gi | 19697861 | AY059526 | influenza A virus polymerase (RA) segment 3 gene (A / goose / Hong Kong / ww26 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697863 | AY059527 | influenza A virus polymerase (RA) segment 3 gene (A / goose / Hong Kong / ww28 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697865 | AY059528 | influenza A virus polymerase (RA) segment 3 gene (A / duck / Hong Kong / ww381 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697869 | AY059530 | influenza A virus polymerase (RA) segment 3 gene (A / duck / Hong Kong / ww461 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697871 | AY059531 | influenza A virus polymerase (RA) segment 3 gene (A / goose / Hong Kong / ww491 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697873 | AY059532 | influenza A virus polymerase (RA) segment 3 gene (A / duck / Hong Kong / 2986.1 / 2000 (H5N1)), incomplete coding sequence.

gi | 19697875 | AY059533 | influenza A virus polymerase (RA) segment 3 gene (A / goose / Hong Kong / 3014.8 / 2000 (H5N1)), incomplete coding sequence.

gi | 28821204 | AY221566 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / NT873.3 / 01-MB (H5N1)), incomplete coding sequence.

gi | 28821206 | AY221567 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / NT873.3 / 01 (H5N1)), incomplete coding sequence.

gi | 28821208 | AY221568 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / FY150 / 01-MB (HSN1)), incomplete coding sequence.

gi | 28821210 | AY221569 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / FY150 / 01 (H5N1)), incomplete coding sequence.

gi | 28821212 | AY221570 | influenza A virus polymerase (RA) gene (A / pheasant / Hong Kong / FY155 / 01-MB (H5N1)), incomplete coding sequence.

gi | 28821214 | AY221571 | influenza A virus polymerase (RA) gene (A / pheasant / Hong Kong / FY155 / 01 (H5N1)), incomplete coding sequence.

gi | 28821216 | AY221572 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / YU822.2 / 01-MB (H5N1)), incomplete coding sequence.

gi | 28821218 | AY221573 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / YU822.2 / 01 (H5N1)), incomplete coding sequence.

gi | 28821220 | AY221574 | influenza A virus polymerase (RA) gene (A / chicken / Hong Kong / YU562 / 01 (H5N1)), incomplete coding sequence.

gi | 41207483 | AY518365 | influenza A virus polymerase (RA) gene (A / duck / China / E319-2 / 03 (H5N1)), full-length coding sequence.

gi | 51094114 | AY551934 | influenza A virus polymerase (RA) gene (A / chicken / Patom Highlands / Thailand / CU-K2 / 04 (H5N1)), full-length coding sequence.

gi | 47834839 | AY576406 | influenza A virus polymerase (RA) gene (A / GS / HK / 739.2 / 02 (H5N1)), incomplete coding sequence.

gi | 47834841 | AY576407 | influenza A virus polymerase (RA) gene (A / Eg / HK / 757.3 / 02 (H5N1)), incomplete coding sequence.

gi | 47834843 | AY576408 | influenza A virus polymerase (RA) gene (A / G.H / HK / 793.1 / 02 (H5N1)), incomplete coding sequence.

gi | 47834845 | AY576409 | influenza A virus polymerase (RA) gene (A / Dk / HK / 821/02 (H5N1)), incomplete coding sequence.

gi | 47834847 | AY576410 | influenza A virus polymerase (RA) gene (A / Ck / HK / 31.4 / 02 (H5N1)), full-length coding sequence.

gi | 47834849 | AY576411 | influenza A virus polymerase (RA) gene (A / Ck / HK / 61.9 / 02 (H5N1)), full-length coding sequence.

gi | 47834851 | AY576412 | influenza A virus polymerase (RA) gene (A / Ck / HK / YU777 / 02 (H5N1)), full-length coding sequence.

gi | 47834853 | AY576413 | influenza A virus polymerase (RA) gene (A / Ck / HK / 96.1 / 02 (H5N1)), incomplete coding sequence.

gi | 47834855 | AY576414 | influenza A virus polymerase (RA) gene (A / chicken / HK / 409.1 / 02 (H5N1)), incomplete coding sequence.

gi | 47834857 | AY576415 | influenza A virus polymerase (RA) gene (A / Ph / HK / sv674.15 / 02 (H5N1)), full-length coding sequence.

gi | 47156478 | AY585462 | mRNA polymerase (RA) of influenza A virus (A / duck / Fujiyan / 01/2002 (H5N1)), full-length coding sequence.

gi | 47156480 | AY585463 | influenza A virus polymerase (RA) mRNA (A / duck / Fujiyan / 13/2002 (H5N1)), full-length coding sequence.

gi | 47156482 | AY585464 | mRNA polymerase (RA) of influenza A virus (A / duck / Fujiyan / 17/2001 (H5N1)), full-length coding sequence.

gi | 47156484 | AY585465 | mRNA polymerase (RA) of influenza A virus (A / duck / Fujiyan / 19/2000 (H5N1)), full-length coding sequence.

gi | 47156486 | AY585466 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)), full-length coding sequence.

gi | 47156488 | AY585467 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)), full-length coding sequence.

gi | 47156490 | AY585468 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)), full-length coding sequence.

gi | 47156492 | AY585469 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)), full-length coding sequence.

gi | 47156494 | AY585470 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)), full-length coding sequence.

gi | 47156496 | AY585471 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)), full-length coding sequence.

gi | 47156498 | AY585472 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)), full-length coding sequence.

gi | 47156500 | AY585473 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)), full-length coding sequence.

gi | 47156502 | AY585474 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)), full-length coding sequence.

gi | 47156504 | AY585475 | mRNA polymerase (RA) of influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)), full-length coding sequence.

gi | 47156506 | AY585476 | mRNA polymerase (RA) of influenza A virus (A / duck / Shanghai / 08/2001 (H5N1)), full-length coding sequence.

gi | 47156508 | AY585477 | mRNA polymerase (RA) of influenza A virus (A / duck / Shanghai / 13/2001 (H5N1)), full-length coding sequence.

gi | 47156510 | AY585478 | mRNA polymerase (RA) of influenza A virus (A / duck / Shanghai / 35/2002 (H5N1)), full-length coding sequence.

gi | 47156512 | AY585479 | influenza virus polymerase (RA) mRNA (A / duck / Shanghai / 37/2002 (H5N1)), full-length coding sequence.

gi | 47156514 | AY585480 | mRNA polymerase (RA) of influenza A virus (A / duck / Shanghai / 38/2001 (H5N1)), full-length coding sequence.

gi | 47156516 | AY585481 | mRNA polymerase (RA) of influenza A virus (A / duck / Zheyan / 11/2000 (H5N1)), full-length coding sequence.

gi | 47156518 | AY585482 | mRNA polymerase (RA) of influenza A virus (A / duck / Zheyan / 52/2000 (H5N1)), full-length coding sequence.

gi | 47716770 | AY609311 | Influenza A virus segment 3 (A / chicken / Guangdong / 174/04 (H5N1)), full length sequence.

gi | 50313026 | AY651597 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Indonesia / 4/2004 (H5N1)), incomplete coding sequence.

gi | 50313028 | AY651598 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Indonesia / 5/2004 (H5N1)), incomplete coding sequence.

gi | 50313030 | AY651599 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Indonesia / 2A / 2003 (H5N1)), incomplete coding sequence.

gi | 50313032 | AY651600 | influenza A virus polymerase acid protein (RA) gene (A / Dk / Indonesia / MS / 2004 (H5N1)), incomplete coding sequence.

gi | 50313034 | AY651601 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Indonesia / BL / 2003 (H5N1)), incomplete coding sequence.

gi | 50313036 | AY651602 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Indonesia / PA / 2003 (H5N1)), incomplete coding sequence.

gi | 50313038 | AY651603 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Thailand / 1/2004 (H5N1)), incomplete coding sequence.

gi | 50313040 | AY651604 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Thailand / 73/2004 (H5N1)), incomplete coding sequence.

gi | 50313042 | AY651605 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Thailand / 9.1 / 2004 (H5N1)), incomplete coding sequence.

gi | 50313044 | AY651606 | influenza A virus polymerase acid protein (RA) gene (A / Qa / Thailand / 57/2004 (H5N1)), incomplete coding sequence.

gi | 50313046 | AY651607 | influenza A virus polymerase acid protein (RA) gene (A / avian / Thailand / 3.1 / 2004 (H5N1)), incomplete coding sequence.

gi | 50313048 | AY651608 | influenza A virus polymerase acid protein (RA) gene (A / Dk / Thailand / 71.1 / 2004 (H5N1)), incomplete coding sequence.

gi | 50313050 | AY651609 | influenza A virus polymerase acid protein (RA) gene (A / Gs / Thailand / 79/2004 (H5N1)), incomplete coding sequence.

gi | 50313060 | AY651614 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / 33/2004 (H5N1)), incomplete coding sequence.

gi | 50313062 | AY651615 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / 35/2004 (H5N1)), incomplete coding sequence.

gi | 50313064 | AY651616 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / 36/2004 (H5N1)), incomplete coding sequence.

gi | 50313066 | AY651617 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / 37/2004 (H5N1)), incomplete coding sequence.

gi | 50313068 | AY651618 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / 38/2004 (H5N1)), incomplete coding sequence.

gi | 50313070 | AY651619 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / 39/2004 (H5N1)), incomplete coding sequence.

gi | 50313072 | AY651620 | influenza A virus polymerase acid protein (RA) gene (A / Ck / Vietnam / C57 / 2004 (H5N1)), incomplete coding sequence.

gi | 50313074 | AY651621 | influenza A virus polymerase acid protein (RA) gene (A / Dk / Vietnam / 11/2004 (H5N1)), incomplete coding sequence.

gi | 50313076 | AY651622 | influenza A virus polymerase acid protein (RA) gene (A / Gf / HK / 38/2002 (H5N1)), full-length coding sequence.

gi | 50313078 | AY651623 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / 31.2 / 2002 (H5N1)), full-length coding sequence.

gi | 50313080 | AY651624 | influenza A virus polymerase acid protein (RA) gene (A / chicken / HK / 37.4 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313082 | AY651625 | influenza A virus polymerase acid protein (RA) gene (A / SCk / HK / YU100 / 2002 (H5N1)), full-length coding sequence.

gi | 50313084 | AY651626 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / YU22 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313086 | AY651627 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / 3176.3 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313088 | AY651628 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / 3169.1 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313090 | AY651629 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / FY157 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313092 | AY651630 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / YU324 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313094 | AY651631 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / 2133.1 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313096 | AY651632 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / NT93 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313098 | AY651633 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / SSP141 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313100 | AY651634 | influenza A virus polymerase acid protein (RA) gene (A / Ck / HK / WF157 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313102 | AY651635 | influenza A virus polymerase acid protein (RA) gene (A / black-headed gull / HK / 12.1 / 2003 (H5N1)), incomplete coding sequence.

gi | 50313104 | AY651636 | influenza A virus polymerase acid protein (RA) gene (A / gray heron / HK / 861.1 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313106 | AY651637 | influenza A virus polymerase acid protein (RA) gene (A / feral pigeon / HK / 862.7 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313108 | AY651638 | influenza A virus polymerase acid protein (RA) gene (A / tree sparrow / HK / 864/2002 (H5N1)), incomplete coding sequence.

gi | 50313110 | AY651639 | influenza A virus polymerase acid protein (RA) gene (A / teal / China / 2978.1 / 2002 (H5N1)), incomplete coding sequence.

gi | 50313112 | AY651640 | influenza A virus polymerase acid protein (RA) gene (A / Peregrine Falcon / HK / D0028 / 2004 (H5N1)), incomplete coding sequence.

gi | 50313114 | AY651541 | influenza A virus polymerase acid protein (RA) gene (A / Dk / HN / 5806/2003 (H5N1)), incomplete coding sequence.

gi | 50313116 | AY651642 | influenza A virus polymerase acid protein (RA) gene (A / Dk / HN / 303/2004 (H5N1)), incomplete coding sequence.

gi | 50313118 | AY651543 | influenza A virus polymerase acid protein (RA) gene (A / Dk / HN / 101/2004 (H5N1)), incomplete coding sequence.

gi | 50313120 | AY651644 | influenza A virus polymerase acid protein (RA) gene (A / Dk / ST / 4003/2003 (H5N1)), incomplete coding sequence.

gi | 50313122 | AY651645 | influenza A virus polymerase acid protein (RA) gene (A / Ph / ST / 44/2004 (H5N1)), incomplete coding sequence.

gi | 50313124 | AY651646 | influenza A virus polymerase acid protein (RA) gene (A / Ck / ST / 4231/2003 (H5N1)), incomplete coding sequence.

gi | 50313126 | AY651647 | influenza A virus polymerase acid protein (RA) gene (A / Dk / YN / 6255/2003 (H5N1)), incomplete coding sequence.

gi | 50313128 | AY651648 | influenza A virus polymerase acid protein (RA) gene (A / Dk / YN / 6445/2003 (H5N1)), incomplete coding sequence.

gi | 50313130 | AY651649 | influenza A virus polymerase acid protein (RA) gene (A / Ck / YN / 115/2004 (H5N1)), incomplete coding sequence.

gi | 50313132 | AY651650 | influenza A virus polymerase acid protein (RA) gene (A / Ck / YN / 374/2004 (H5N1)), incomplete coding sequence.

gi | 50365724 | AY653198 | Influenza A virus segment 3 (A / chicken / Zhilin / 9/2004 (H5N1)), full length sequence.

gi | 56548923 | AY676029 | influenza A virus polymerase (RA) gene (A / duck / Hong Kong / 821/02 (H5N1)), full-length coding sequence.

gi | 56548925 | AY676030 | influenza A virus polymerase (RA) gene (A / white egret / Hong Kong / 757.2 / 03 (H5N1)), full-length coding sequence.

gi | 56548927 | AY676031 | influenza A virus polymerase (RA) gene (A / chicken / Korea / ES / 03 (H5N1)), full-length coding sequence.

gi | 56548929 | AY676032 | influenza A virus polymerase (RA) gene (A / duck / Korea / ESD1 / 03 (H5N1)), full-length coding sequence.

gi | 50956625 | AY684705 | influenza A virus polymerase (RA) gene (A / chicken / Hubei / 327/2004 (H5N1)), full-length coding sequence.

gi | 56119221 | AY720944 | influenza A virus polymerase acid protein (RA) gene (A / chicken / Vietnam / DT-171/2004 (H5N1)), incomplete coding sequence.

gi | 56119227 | AY720947 | influenza A virus polymerase acid protein (RA) gene (A / duck / Vietnam / TG-007A / 2004 (H5N1)), incomplete coding sequence.

gi | 57924419 | AY724784 | influenza A virus polymerase (RA) gene (A / chicken / Vietnam / HCM-022/2004 (H5N1)), incomplete coding sequence.

gi | 57924480 | AY724786 | influenza A virus polymerase (RA) gene (A / chicken / Vietnam / DN-045/2004 (H5N1)), incomplete coding sequence.

gi | 57924569] | AY724788 | influenza A virus polymerase (RA) gene (A / chicken / Vietnam / VL-008/2004 (H5N1)), incomplete coding sequence.

gi | 57924680 | AY724790 | influenza A virus polymerase (RA) gene (A / chicken / Vietnam / AG-010/2004 (H5N1)), incomplete coding sequence.

gi | 57924765 | AY724792 | influenza A virus polymerase (RA) gene (A / chicken / Vietnam / DT-015/2004 (H5N1)), incomplete coding sequence.

gi | 57924882 | AY724796 | influenza A virus polymerase (RA) gene (A / chicken / Vietnam / LA-024/2004 (H5N1)), incomplete coding sequence.

gi | 57915971 | AY737288 | Influenza A virus segment 3 (A / chicken / Guangdong / 191/04 (H5N1)), full length sequence.

gi | 57916018 | AY737295 | Influenza A virus segment 3 (A / chicken / Guangdong / 178/04 (H5N1)), full length sequence.

gi | 57916074 | AY737303 | Influenza A virus segment 3 (A / duck / Guangdong / 173/04 (H5N1)), full length sequence.

gi | 55233234 | AY770082 | influenza A virus polymerase (RA) gene (A / chicken / Hubei / 489/2004 (H5N1)), full-length coding sequence.

gi | 54873465 | AY770995 | influenza A virus polymerase gene (A / chicken / Attaya / Thailand / CU-23/04 (H5N1)), incomplete coding sequence.

gi | 58618433 | AY818133 | influenza A virus polymerase protein (RA) gene (A / chicken / Vietnam / C58 / 04 (H5N1)), full-length coding sequence.

gi | 58618435 | AY818134 | influenza A virus polymerase (RA) gene (A / quail / Vietnam / 36/04 (H5N1)), full-length coding sequence.

gi | 58374187 | AY856863 | Influenza A virus segment 3 (A / duck / Shandu / 093/2004 (H5N1)), full length sequence.

gi | 58531136 | AB188823 | influenza A virus polymerase acid protein RA gene (A / chicken / Kyoto / 3/2004 (H5N1)), full-length coding sequence.

gi | 58531154 | AB189052 | influenza A virus polymerase acid protein RA gene (A / raven / Kyoto / 53/2004 (H5N1)), full-length coding sequence.

gi | 58531170 | AB189059 | influenza A virus polymerase acid protein RA gene (A / raven / Osaka / 102/2004 (H5N1)), full-length coding sequence.

gi | 3335418 | AF046087 | influenza A virus polymerase acid protein (RA) gene (A / chicken / Hong Kong / 220/97 (H5N1)), incomplete coding sequence.

gi | 6048895 | AF098604 | influenza A virus protein (PA) gene (A / chicken / Hong Kong / 258/97 (H5N1)), full-length coding sequence.

gi | 6048897 | AF098605 | influenza A virus protein (PA) gene (A / chicken / Hong Kong / y388 / 97 (H5N1)), full-length coding sequence.

gi | 6048899 | AF098606 | influenza A virus protein (PA) gene (A / chicken / Hong Kong / 728/97 (H5N1)), full-length coding sequence.

gi | 6048901 | AF098607 | influenza A virus protein (PA) gene (A / chicken / Hong Kong / 786/97 (H5N1)), full-length coding sequence.

gi | 6048903 | AF098608 | influenza A virus protein (PA) gene (A / chicken / Hong Kong / 915/97 (H5N1)), full-length coding sequence.

gi | 6048905 | AF098609 | influenza A virus protein (PA) gene (A / duck / Hong Kong / p46 / 97 (H5N1)), full-length coding sequence.

gi | 6048907 | AF098610 | influenza A virus RA (RA) gene gene (A / duck / Hong Kong / y283 / 97 (H5N1)), full-length coding sequence.

gi | 6048909 | AF098611 | influenza A virus protein (PA) gene (A / goose / Hong Kong / w355 / 97 (H5N1)), full-length coding sequence.

gi | 5805280 | AF144302 | influenza A virus polymerase PA (PA) gene (A / goose / Guangdong / 1/96 (H5N1)), full-length coding sequence.

gi | 9863880 | AF216715 | influenza A virus polymerase acid protein gene (A / environment / Hong Kong / 437-4 / 99 (H5N1)), full-length coding sequence.

gi | 9863899 | AF216723 | influenza A virus polymerase acid protein gene (A / environment / Hong Kong / 437-6 / 99 (H5N1)), full-length coding sequence.

gi | 9863917 | AF216731 | influenza A virus polymerase acid protein gene (A / environment / Hong Kong / 437-8 / 99 (H5N1)), full-length coding sequence.

gi | 34597776 | AY303660 | influenza A virus polymerase acid protein gene (A / chicken / Chile / 176822/02 (H7N3)), full-length coding sequence.

gi | 34597778 | AY303661 | influenza A virus polymerase acid protein gene (A / chicken / Chile / 4957/02 (H7N3)), full-length coding sequence.

gi | 34597780 | AY303662 | influenza A virus polymerase acid protein gene (A / chicken / Chile / 4322/02 (H7N3)), incomplete coding sequence.

gi | 47680912 | AY586431 | influenza A virus PA gene (A / mallard / Italy / 43/01 (H7N3)), incomplete coding sequence.

gi | 47680914 | AY586432 | influenza A virus PA gene (A / mallard / Italy / 33/01 (H7N3)), incomplete coding sequence.

gi | 47680916 | AY586433 | influenza A virus PA gene (A / turkey / Italy / 220158/2002 (H7N3)), incomplete coding sequence.

gi | 47680918 | AY586434 | influenza A virus PA gene (A / turkey / Italy / 214845/02 (H7N3)), incomplete coding sequence.

gi | 47834370 | AY616764 | influenza A virus polymerase acid protein 2 (PA) gene (A / chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

gi | 50542647 | AY646083 | Influenza A virus polymerase acid protein 2 (PA) gene (A / chicken / British Columbia / GSC_B_04 / H7N3), full-length coding sequence.

gi | 50083049 | AY648292 | influenza A virus polymerase acid protein 2 (PA) gene (A / GSC_ chicken_B / British Columbia / 04 (H7N3)), full-length coding sequence.

gi | 50059192 | AY650275 | influenza A virus polymerase acid protein 2 (PA) gene (A / GSC_ chicken / British Columbia / 04 (H7N3)), full-length coding sequence.

gi | 9988639 | AF268109 | influenza A virus polymerase protein PA gene (A / Icelandic sandpiper / Delaware / 259/94 (H7N7)), incomplete coding sequence.

gi | 40353080 | AJ619677 | influenza A virus polymerase complex PA subunit gene (A / chicken / Germany / R28 / 03 (H7N7)), genomic RNA.

gi | 37813167 | AY342415 | influenza A virus polymerase protein A gene (A / Netherlands / 124/03 (H7N7)), incomplete coding sequence.

gi | 37813169 | AY342416 | influenza A virus polymerase protein A gene (A / Netherlands / 126/03 (H7N7)), incomplete coding sequence.

gi | 37813171 | AY342417 | influenza A virus polymerase protein A gene (A / Netherlands / 127/03 (H7N7)), incomplete coding sequence.

gi | 37813173 | AY342418 | influenza A virus polymerase protein A gene (A / Netherlands / 219/03 (H7N7)), full-length coding sequence.

gi | 37813175 | AY342419 | influenza A virus polymerase protein A gene (A / Netherlands / 033/03 (H7N7)), full-length coding sequence.

gi | 37813177 | AY342420 | influenza A virus polymerase protein A gene (A / chicken / Netherlands / 1/03 (H7N7)), full-length coding sequence.

gi | 13383274 | AB049157 | influenza A virus polymerase acid protein PA gene (A / parrot / Chiba / 1/97 (H9N2)), full-length coding sequence.

gi | 13383276 | AB049158 | influenza A virus polymerase acid protein A gene (A / parrot / Narita / 92A / 98 (H9N2)), full-length coding sequence.

gi | 33318154 | AF508662 | influenza A virus polymerase PA (PA) segment 3 gene (A / ostrich / South Africa / 9508103/95 (H9N2)), full-length coding sequence.

gi | 33318156 | AF508663 | influenza A virus polymerase segment PA (PA) gene 3 gene (A / chicken / Pakistan / 4/99 (H9N2)), full-length coding sequence.

gi | 33318158 | AF508664 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Pakistan / 5/99 (H9N2)), incomplete coding sequence.

gi | 33318160 | AF508665 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Germany / R45 / 98 (H9N2)), full-length coding sequence.

gi | 33318162 | AF508666 | influenza A virus polymerase PA (PA) segment 3 gene (A / duck / Germany / 113/95 (H9N2)), full-length coding sequence.

gi | 33318164 | AF508667 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Iran / 11T / 99 (H9N2)), incomplete coding sequence.

gi | 33318166 | AF508668 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Saudi Arabia / 532/99 (H9N2)), full-length coding sequence.

gi | 33318168 | AF508669 | influenza A virus polymerase segment PA (PA) gene 3 gene (A / pheasant / Ireland / PV18 / 97 (H9N2)), full-length coding sequence.

gi | 33318170 | AF508670 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Korea / 99029/99 (H9N2)), full-length coding sequence.

gi | 33318172 | AF508671 | influenza A virus polymerase segment PA (PA) gene 3 gene (A / chicken / Beijin / 8/98 (H9N2)), full-length coding sequence.

gi | 33318174 | AF508672 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Guangdong / 10/00 (H9N2)), full-length coding sequence.

gi | 33318176 | AF508673 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Guangdong / 11/97 (H9N2)), full-length coding sequence.

gi | 33318178 | AF508674 | influenza A virus polymerase segment PA (PA) gene 3 gene (A / chicken / Hebei / 4/98 (H9N2)), full-length coding sequence.

gi | 33318180 | AF508675 | influenza A virus polymerase segment PA (PA) gene 3 gene (A / chicken / Heylonyan / 10/97 (H9N2)), full-length coding sequence.

gi | 33318182 | AF508676 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Henan / 62/00 (H9N2)), incomplete coding sequence.

gi | 33318184 | AF508677 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Ningsia / 5/99 (H9N2)), full-length coding sequence.

gi | 33318186 | AF508678 | gene of polymerase segment 3 (PA) of influenza A virus (A / chicken / Xihuan / 5/97 (H9N2)), full-length coding sequence.

gi | 33318188 | AF508679 | influenza A virus polymerase segment PA (PA) gene 3 gene (A / chicken / Shandu / 6/96 (H9N2)), incomplete coding sequence.

gi | 33318190 | AF508680 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Shiyazhuan / 2/99 (H9N2)), incomplete coding sequence.

gi | 33318192 | AF508681 | influenza A virus polymerase PA (PA) segment 3 gene (A / chicken / Shenzhen / 9/97 (H9N2)), full-length coding sequence.

gi | 33318194 | AF508682 | influenza A virus polymerase PA (PA) segment 3 gene (A / duck / Nanyang / 1/97 (H9N2)), full-length coding sequence.

gi | 33318196 | AF508683 | influenza A virus polymerase PA (PA) segment 3 gene (A / quail / Shanghai / 8/96 (H9N2)), incomplete coding sequence.

gi | 31339541 | AF523446 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 1043/00 (H9N2)), incomplete coding sequence.

gi | 31339543 | AF523447 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 1042/00 (H9N2)), incomplete coding sequence.

gi | 31339545 | AF523448 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 2088/01 (H9N2)), incomplete coding sequence.

gi | 31339547 | AF523449 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 830/00 (H9N2)), incomplete coding sequence.

gi | 31339549 | AF523450 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 1796/00 (H9N2)), incomplete coding sequence.

gi | 31339551 | AF523451 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 2143/00 (H9N2)), incomplete coding sequence.

gi | 31339553 | AF523452 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 2134/00 (H9N2)), incomplete coding sequence.

gi | 31339555 | AF523453 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 2144/00 (H9N2)), incomplete coding sequence.

gi | 31339557 | AF523454 | influenza A virus polymerase (PA) gene (A / wild duck / Shantu / 4808/01 (H9N2)), incomplete coding sequence.

gi | 31339559 | AF523455 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 1881/00 (H9N2)), incomplete coding sequence.

gi | 31339561 | AF523456 | influenza A virus polymerase (PA) gene (A / duck / Shantu / 2102/00 (H9N2)), incomplete coding sequence.

gi | 31339563 | AF523457 | influenza A virus polymerase (PA) gene (A / duck / Hong Kong / 289/78 (H9N2)), incomplete coding sequence.

gi | 31339565 | AF523458 | influenza A virus polymerase (PA) gene (A / duck / Hong Kong / 610/79 (H9N2)), incomplete coding sequence.

gi | 31339567 | AF523459 | influenza A virus polymerase (PA) gene (A / duck / Hong Kong / 86/76 (H9N2)), incomplete coding sequence.

gi | 31339569 | AF523460 | influenza A virus polymerase (PA) gene (A / duck / Hong Kong / 366/78 (H9N2)), incomplete coding sequence.

gi | 22759040 | AF536669 | the influenza A virus PA gene (A / chicken / Beijin / 1/95 (H9N2)), an incomplete coding sequence.

gi | 22759042 | AF536670 | the influenza A virus PA gene (A / chicken / Beijin / 2/97 (H9N2)), an incomplete coding sequence.

gi | 22759044 | AF536671 | the influenza A virus PA gene (A / chicken / Beijin / 3/99 (H9N2)), an incomplete coding sequence.

gi | 22759046 | AF536672 | influenza A virus PA gene (A / chicken / Guangdong / 97 (H9N2)), incomplete coding sequence.

gi | 22759048 | AF536673 | the influenza A virus PA gene (A / chicken / Hebei / 1/96 (H9N2)), an incomplete coding sequence.

gi | 22759050 | AF536674 | the influenza A virus PA gene (A / chicken / Hebei / 2/98 (H9N2)), an incomplete coding sequence.

gi | 22759052 | AF536675 | the influenza A virus PA gene (A / chicken / Hebei / 3/98 (H9N2)), an incomplete coding sequence.

gi | 22759054 | AF536676 | influenza A virus PA gene (A / chicken / Henan / 98 (H9N2)), incomplete coding sequence.

gi | 22759056 | AF536677 | influenza A virus PA gene (A / chicken / Liaoning / 99 (H9N2)), incomplete coding sequence.

gi | 22759058 | AF536678 | influenza A virus PA gene (A / chicken / Shandu / 98 (H9N2)), incomplete coding sequence.

gi | 12038897 | AJ291397 | influenza A virus polymerase PA gene (A / chicken / Pakistan / 2/99 (H9N2)), genomic RNA.

gi | 18496121 | AJ427863 | incomplete gene for the polymerase PA protein of influenza A virus PA (A / quail / Hong Kong / FY298 / 00 (H9N2)), genomic RNA.

gi | 27465911 | AY180650 | gene of the polymerase subunit PA (PA) of influenza virus strain A / duck / Nanhan / 11-392 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465913 | AY180651 | gene of the polymerase subunit PA (PA) of influenza virus strain A / duck / Nanhan / 11-290 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465915 | AY180652 | gene of the polymerase subunit PA (PA) of influenza virus strain A / chicken / Nanhan / 1-0016 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465917 | AY180653 | gene of the polymerase subunit PA (PA) of influenza virus strain A / duck / Nanhan / 11-197 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465937 | AY180663 | gene of the polymerase subunit PA (PA) of the influenza virus strain A / pigeon / Nanhan / 2-0461 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465941 | AY180665 | gene of the polymerase subunit PA (PA) of influenza virus strain A / chicken / Nanhan / 4-301 / 2001 (H9N2), an incomplete coding sequence.

gi | 27465943 | AY180666 | gene polymerase subunit PA (PA) of influenza virus strain A / chicken / Nanhan / 4-361 / 2001 (H9N2), incomplete coding sequence.

gi | 27465961 | AY180675 | gene of the polymerase subunit PA (PA) of influenza strain A strain / wild duck / Nanhan / 2-0480 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465983 | AY180686 | gene of the polymerase subunit PA (PA) of the influenza virus strain A / duck / Nanhan / 1-0070 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465989 | AY180689 | gene of the polymerase subunit PA (PA) of influenza virus strain A / duck / Nanhan / 10-389 / 2000 (H9N2), an incomplete coding sequence.

gi | 27465993 | AY180691 | gene of the polymerase subunit PA (PA) of influenza virus strain A / pigeon / Nanhan / 11-145 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466001 | AY180695 | gene of the polymerase subunit PA (PA) of influenza virus strain A / quail / Nanhan / 2-0460 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466003 | AY180696 | gene of the polymerase subunit PA (PA) of influenza virus strain A / quail / Nanhan / 4-040 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466009 | AY180699 | gene of the polymerase subunit PA (PA) of influenza virus strain A / chicken / Nanhan / 4-010 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466015 | AY180702 | gene of the polymerase subunit PA (PA) of influenza virus strain A / duck / Nanhan / 7-092 / 2000 (H9N2), an incomplete coding sequence.

gi | 27466019 | AY180704 | gene of the polymerase subunit PA (PA) of influenza virus strain A / pigeon / Nanhan / 7-058 / 2000 (H9N2), an incomplete coding sequence.

gi | 30025973 | AY253752 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Shanghai / F / 98 (H9N2)), full-length coding sequence.

gi | 49357051 | AY633169 | influenza A virus polymerase protein A (PA) gene (A / mallard / Alberta / 17/91 (H9N2)), incomplete coding sequence.

gi | 49357079 | AY633281 | influenza A virus polymerase protein A (PA) gene (A / mallard / Alberta / 321/88 (H9N2)), incomplete coding sequence.

gi | 49357083 | AY633297 | influenza A virus polymerase protein A (PA) gene (A / mallard / Alberta / 11/91 (H9N2)), incomplete coding sequence.

gi | 54301528 | AY664755 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / CSW153 / 03 (H9N2)), incomplete coding sequence.

gi | 54301530 | AY664756 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / AP45 / 03 (H9N2)), incomplete coding sequence.

gi | 54301532 | AY664757 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / BD90 / 03 (H9N2)), incomplete coding sequence.

gi | 54301534 | AY664758 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / CSW291 / 03 (H9N2)), incomplete coding sequence.

gi | 54301536 | AY664759 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / CSW304 / 03 (H9N2)), incomplete coding sequence.

gi | 54301538 | AY664760 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / FY23 / 03 (H9N2)), incomplete coding sequence.

gi | 54301540 | AY664761 | influenza A virus polymerase acid protein (PA) gene (A / Guinea fowl / Hong Kong / NT101 / 03 (H9N2)), incomplete coding sequence.

gi | 54301542 | AY664762 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / NT142 / 03 (H9N2)), incomplete coding sequence.

gi | 54301544 | AY664763 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / SF1 / 03 (H9N2)), incomplete coding sequence.

gi | 54301546 | AY664764 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / SSP101 / 03 (H9N2)), incomplete coding sequence.

gi | 54301548 | AY664765 | a gene similar to the influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / TP38 / 03 (H9N2)), full length sequence.

gi | 54301549 | AY664766 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / WF126 / 03 (H9N2)), incomplete coding sequence.

gi | 54301551 | AY664767 | influenza A virus polymerase acid protein (PA) gene (A / pigeon / Hong Kong / WF53 / 03 (H9N2)), incomplete coding sequence.

gi | 54301553 | AY664768 | influenza A virus polymerase acid protein (PA) gene (A / pheasant / Hong Kong / WF54 / 03 (H9N2)), incomplete coding sequence.

gi | 54301555 | AY664769 | influenza A virus polymerase acid protein (PA) gene (A / Guinea fowl / Hong Kong / NT184 / 03 (H9N2)), incomplete coding sequence.

gi | 54301557 | AY664770 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / WF120 / 03 (H9N2)), incomplete coding sequence.

gi | 54301559 | AY664771 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / NT366 / 03 (H9N2)), incomplete coding sequence.

gi | 54301561 | AY664772 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / SSP418 / 03 (H9N2)), incomplete coding sequence.

gi | 54301563 | AY664773 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Hong Kong / YU427 / 03 (H9N2)), incomplete coding sequence.

gi | 55793682 | AY800238 | influenza A virus polymerase acid protein (PA) gene (A / chicken / Korea / S1 / 2003 (H9N2)), full-length coding sequence.

gi | 58429718 | AY862678 | influenza A virus PA (PA) gene (A / silk chicken / Korea / S3 / 03 (H9N2)), incomplete coding sequence.

gi | 58429720 | AY862679 | the influenza A virus PA (PA) gene (A / chicken / Korea / S4 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429722 | AY862680 | influenza A virus PA (PA) gene (A / chicken / Korea / S5 / 03 (H9N2)), full-length coding sequence.

gi | 58429724 | AY862681 | the influenza A virus PA (PA) gene (A / chicken / Korea / S12 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429726 | AY862682 | the influenza A virus PA (PA) gene (A / duck / Korea / S13 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429728 | AY862683 | influenza A virus PA (PA) gene (A / pigeon / Korea / S14 / 03 (H9N2)), incomplete coding sequence.

gi | 58429730 | AY862684 | the influenza A virus PA (PA) gene (A / chicken / Korea / S15 / 03 (H9N2)), an incomplete coding sequence.

gi | 58429732 | AY862685 | influenza A virus PA (PA) gene (A / chicken / Korea / S16 / 03 (H9N2)), incomplete coding sequence.

gi | 58429734 | AY862686 | the influenza A virus PA (PA) gene (A / chicken / Korea / S18 / 03 (H9N2)), an incomplete coding sequence.

gi | 5732356 | AF156444 | influenza A virus polymerase (PA) segment 3 gene (A / chicken / Hong Kong / G9 / 97 (H9N2)), incomplete coding sequence.

gi | 5732358 | AF156445 | influenza A virus polymerase (PA) segment 3 gene (A / chicken / Hong Kong / G23 / 97 (H9N2)), full-length coding sequence.

gi | 5732360 | AF156446 | influenza A virus polymerase (PA) segment 3 gene (A / pigeon / Hong Kong / Y233 / 97 (H9N2)), incomplete coding sequence.

gi | 5732362 | AF156447 | influenza A virus polymerase (PA) segment 3 gene (A / duck / Hong Kong / Y280 / 97 (H9N2)), incomplete coding sequence.

gi | 5732364 | AF156448 | influenza A virus polymerase (PA) segment 3 gene (A / duck / Hong Kong / Y439 / 97 (H9N2)), incomplete coding sequence.

gi | 5732366 | AF156449 | influenza A virus polymerase (PA) segment 3 gene (A / quail / Hong Kong / G1 / 97 (H9N2)), incomplete coding sequence.

gi | 5732368 | AF156450 | influenza A virus polymerase (PA) segment 3 gene (A / chicken / Hong Kong / 739/94 (H9N2)), incomplete coding sequence.

gi | 5732370 | AF156451 | influenza A virus polymerase (PA) segment 3 gene (A / quail / Hong Kong / | AF157 / 92 (H9N2)), incomplete coding sequence.

gi | 5732372 | AF156452 | influenza A virus polymerase (PA) segment 3 gene (A / chicken / Beijin / 1/94 (H9N2)), incomplete coding sequence.

gi | 5732374 | AF156453 | influenza A virus polymerase (PA) segment 3 gene (A / chicken / Korea / 38349-p96323 / 96 (H9N2)), incomplete coding sequence.

gi | 5732376 | AF156454 | influenza A virus polymerase (PA) segment 3 gene (A / chicken / Korea / 25232-96006 / 96 (H9N2)), incomplete coding sequence.

gi | 5732378 | AF156455 | influenza A virus polymerase (PA) segment 3 gene (A / plover / Delaware / 9/96 (H9N2)), incomplete coding sequence.

gi | 5732380 | AF156456 | influenza A virus polymerase (PA) segment 3 gene (A / quail / Arkansas / 29209-1 / 93 (H9N2)), incomplete coding sequence.

gi | 5732382 | AF156457 | influenza A virus polymerase (PA) segment 3 gene (A / turkey / California / 189/66 (H9N2)), incomplete coding sequence.

gi | 12060671 | AF222642 | influenza A virus PA (PA) segment 3 gene (A / quail / Hong Kong / A17 / 99 (H9N2)), incomplete coding sequence.

gi | 12060673 | AF222643 | influenza A virus PA (PA) segment 3 gene (A / pigeon / Hong Kong / FY6 / 99 (H9N2)), incomplete coding sequence.

gi | 12060675 | AF222644 | influenza A virus PA (PA) segment 3 gene (A / chicken / Hong Kong / NT16 / 99 (H9N2)), incomplete coding sequence.

gi | 12060677 | AF222645 | gene segment 3 PA (PA) of influenza A virus (A / quail / Hong Kong / SSP10 / 99 (H9N2)), an incomplete coding sequence.

gi | 12060679 | AF222646 | influenza A virus segment 3 PA (PA) gene (A / pheasant / Hong Kong / SSP11 / 99 (H9N2)), incomplete coding sequence.

gi | 120606811 | AF222647 | influenza A virus PA (PA) segment 3 gene (A / chicken / Hong Kong / FY20 / 99 (H9N2)), incomplete coding sequence.

gi | 12060683 | AF222648 | influenza A virus segment 3 PA (PA) gene (A / chicken / Hong Kong / KC12 / 99 (H9N2)), incomplete coding sequence.

gi | 12060685 | AF222649 | gene segment 3 PA (PA) of influenza A virus (A / quail / Hong Kong / NT28 / 99 (H9N2)), an incomplete coding sequence.

gi | 12060687 | AF222650 | influenza A virus PA (PA) segment 3 gene (A / chicken / Hong Kong / SF2 / 99 (H9N2)), incomplete coding sequence.

gi | 12060689 | AF222651 | influenza A virus PA (PA) segment 3 gene (A / silk chicken / Hong Kong / SF44 / 99 (H9N2)), incomplete coding sequence.

Claims (73)

1. An iPHK agent that inhibits the expression of the influenza A virus PB2 gene, where the iPHK agent contains a sense strand, where the sense strand contains 15-30 consecutive nucleotides in the inner region that differ from nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, wherein said antisense strand contains in the inner region 15-30 sequential nucleotides that differ from nucleotides of the sequence SEQ ID NO: 428 by no more than one nucleotide. 2. The iPHK agent according to claim 1, wherein the length of said duplex region of the iPHK agent is 19 nucleotide pairs. 3. The iPHK agent according to claim 1, containing a modification that increases the stability of the iPHK agent in a biological sample. 4. The iPHK agent according to claim 1, containing phosphorothioate or a 2'-modified nucleotide. 5. The iPHK agent according to claim 1, containing at least one 5'-uridine-adenine-3 '(5'-ua-3') - a dinucleotide in which the uridine is a 2'-modified nucleotide; at least one 5'-uridine-guanine-3 '(5'-ug-3') is a dinucleotide in which 5'-uridine is a 2'-modified nucleotide; at least one 5'-cytidine-adenine-3 '(5'-ca-3') is a dinucleotide in which 5'-cytidine is a 2'-modified nucleotide; or at least one 5'-uridine-uridin-3 '(5'-uu-3') is a dinucleotide in which 5'-uridine is a 2'-modified nucleotide. 6. The iPHK agent according to claim 4, wherein said 2'-modification is selected from the group consisting of: 2'-deoxy, 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-O -methoxyethyl (2'-O-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2 ' -O-DMAP), 2'-O-dimethylamino-ethyloxyethyl (2'-O-DMAEOE) and 2'-ON-methylacetamide (2'-O-NMA). 7. The iPHK agent according to claim 1, comprising a protruding nucleotide end having 1-4 unpaired nucleotides. 8. The iPHK agent according to claim 7, in which the nucleotide protruding end has 2 or 3 unpaired nucleotides. 9. The iPHK agent according to claim 7, wherein the protruding nucleotide is located at the 3 ′ end of the antisense strand of the iPHK agent. 10. iPHK agent that inhibits the expression of the PB2 gene of influenza A virus, where the iPHK agent contains a sense strand, where the sense strand contains 15-30 consecutive nucleotides in the inner region that differ from nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, wherein said antisense strand contains in the inner region 15-30 consecutive nucleotides that differ from the nucleotides of SEQ ID NO: 428 by no more than one nucleotide containing a cholesterol molecule. 11. The iPHK agent of claim 10, wherein the cholesterol molecule is conjugated to the 3'-end of the sense chain of the iPHK agent. 12. The iPHK agent of claim 1, wherein the iPHK agent is targeted for uptake by lung cells. 13. An iPHK agent that inhibits the expression of the influenza A virus PB2 gene, where the iPHK agent contains a sense strand, wherein said sense strand contains 15-30 sequential nucleotides in the inner region that differ from nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, wherein said antisense strand contains in the inner region 15-30 sequential nucleotides that differ from the nucleotides of SEQ ID NO: 428 by no more than one nucleotide containing at least one non-natural nucleotide base. 14. The iPHK agent of claim 13, wherein the non-naturally occurring nucleotide base is difluorotolyl, nitroindolyl, nitropyrrolyl or nitroimidazolyl. 15. The iPHK agent of claim 13, wherein the non-naturally occurring nucleotide base is difluorotolyl. 16. The iPHK agent of claim 13, wherein only one of the two oligonucleotide chains constituting the double-stranded oligonucleotide contains a non-natural nucleotide base. 17. The iPHK agent of claim 13, wherein both oligonucleotide chains constituting the double-stranded oligonucleotide independently contain a non-natural nucleotide base. 18. The iPHK agent according to claim 1, which reduces the expression of the influenza virus gene by more than 20%, 30%, 40%, 50%, 60%, 70% or 80% in cells in contact with the iPHK agent compared to cells that do not contact the iPHK agent. 19. The iPHK agent according to claim 1, which essentially retains the ability to reduce the number of plaques of influenza A virus formed in the cells found in the plaque assay. 20. The iPHK agent according to claim 1, in which the sense strand consists of the nucleotide sequence of SEQ ID NO: 427, and the antisense sequence consists of the nucleotide sequence of SEQ ID NO: 428. 21. The iPHK agent according to claim 1, containing at least one protruding nucleotide end containing two unpaired nucleotides. 22. The iPHK agent of claim 1, comprising a protruding nucleotide end at each end of the dsRNA, the protruding nucleotide end containing two unpaired nucleotides. 23. The iPHK agent according to claim 1, containing at least one protruding nucleotide end containing two unpaired thymidines. 24. An iPHK agent that inhibits the expression of the influenza A virus PB2 gene and contains a sense strand, wherein said sense strand contains 15-30 consecutive nucleotides that differ from the nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, where the specified antisense chain contains 15-30 consecutive nucleotides that differ from the nucleotides of the sequence SEQ ID NO: 428 by no more than one nucleotide, and where the specified iPHK agent reduces the level of gene expression in Cos7 cells designed for ec Press said gene, more than 20% compared to the expression observed in engineered Cos7 cells that were not contacted with said iPHK-agent. 25. The iPHK agent according to paragraph 24, in which the length of the specified duplex region of the iPHK agent is 19 pairs. 26. The iPHK agent according to paragraph 24, containing a modification that increases the stability of the iPHK agent in a biological sample. 27. The iPHK agent according to paragraph 24, containing phosphorothioate or 2'-modified nucleotide. 28. The iPHK agent according to paragraph 24, containing at least one 5'-uridine-adenine-3 '(5'-ua-3') - dinucleotide, in which the uridine is a 2'-modified nucleotide; at least one 5'-uridine-guanine-3 '(5'-ug-3') is a dinucleotide in which 5'-uridine is a 2'-modified nucleotide; at least one 5'-cytidine-adenine-3 '(5'-ca-3') is a dinucleotide in which 5'-cytidine is a 2'-modified nucleotide; or at least one 5'-uridine-uridin-3 '(5'-uu-3') is a dinucleotide in which 5'-uridine is a 2'-modified nucleotide. 29. The iPHK agent according to claim 27, wherein said 2'-modification is selected from the group consisting of 2'-deoxy, 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-O- methoxyethyl (2'-O-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'- O-DMAP), 2'-O-dimethylamino-ethyloxyethyl (2'-O-DMAEOE) and 2'-ON-methylacetamide (2'-O-NMA). 30. The iPHK agent of claim 24, comprising a protruding nucleotide end having 1-4 unpaired nucleotides. 31. The iPHK agent of claim 30, wherein the nucleotide protruding end has 2 or 3 unpaired nucleotides. 32. The iPHK agent of claim 30, wherein the protruding nucleotide is located at the 3 ′ end of the antisense strand of the iPHK agent. 33. An iPHK agent that inhibits expression of the influenza A virus PB2 gene and contains a sense strand, wherein said sense strand contains 15-30 consecutive nucleotides that differ from the nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, where the specified antisense chain contains 15-30 consecutive nucleotides that differ from the nucleotides of the sequence SEQ ID NO: 428 by no more than one nucleotide, and where the specified iPHK agent reduces the level of gene expression in Cos7 cells designed for ec Press said gene, more than 20% compared to the expression observed in engineered Cos7 cells that were not contacted with said agent iPHK-containing cholesterol molecule. 34. The iPHK agent according to claim 33, wherein the cholesterol molecule is conjugated to the 3 ′ end of the sense strand of the iPHK agent. 35. The iPHK agent of claim 24, wherein the iPHK agent is targeted for capture by lung cells. 36. An iPHK agent that inhibits expression of the influenza A virus PB2 gene and contains a sense strand, wherein said sense strand contains 15-30 consecutive nucleotides that differ from the nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, where the specified antisense chain contains 15-30 consecutive nucleotides that differ from the nucleotides of the sequence SEQ ID NO: 428 by no more than one nucleotide, and where the specified iPHK agent reduces the level of gene expression in Cos7 cells designed for ec Press said gene, more than 20% compared to the expression observed in engineered Cos7 cells that were not contacted with said iPHK-agent containing at least one non-natural nucleotide base. 37. The iPHK agent of claim 36, wherein the non-naturally occurring nucleotide base is difluorotolyl, nitroindolyl, nitropyrrolyl or nitroimidazolyl. 38. The iPHK agent of claim 36, wherein the non-naturally occurring nucleotide base is difluorotolyl. 39. The iPHK agent according to clause 36, in which only one of the two oligonucleotide chains constituting the double-stranded oligonucleotide contains a non-natural nucleotide base. 40. The iPHK agent of claim 36, wherein both oligonucleotide chains constituting the double-stranded oligonucleotide independently contain a non-naturally occurring nucleotide base. 41. The iPHK agent according to paragraph 24, which reduces the expression of the influenza virus gene by more than 20%, 30%, 40%, 50%, 60%, 70% or 80% in cells in contact with the iPHK agent compared to cells that do not contact the iPHK agent. 42. The iPHK agent according to paragraph 24, which essentially retains the ability to reduce the number of plaques of influenza A virus formed in the cells found in the plaque assay. 43. The iPHK agent according to paragraph 24, in which the sense strand consists of the nucleotide sequence of SEQ ID NO: 427, and the antisense sequence consists of the nucleotide sequence of SEQ ID NO: 428. 44. The iPHK agent according to paragraph 24, containing at least one protruding nucleotide end containing two unpaired nucleotides. 45. The iPHK agent of claim 24, comprising a protruding nucleotide end at each end of the dsRNA, the protruding nucleotide end containing two unpaired nucleotides. 46. The iPHK agent according to paragraph 24, containing at least one protruding nucleotide end containing two unpaired thymidines. 47. An iPHK agent that inhibits the expression of the influenza A virus PB2 gene and contains a sense strand and an antisense strand, each strand containing a sequence that consists of 15-30 nucleotides that are essentially identical to SEQ ID NO: 427 and SEQ ID NO : 428, respectively, with the exception that no more than one nucleotide in each strand is replaced with another nucleotide, while the iPHK agent retains the ability to reduce the number of plaques of influenza A virus formed in the cells found in the plaque assay. 48. The iPHK agent according to clause 47, in which the length of the specified duplex region of the iPHK agent is 19 pairs. 49. The iPHK agent according to clause 47, containing a modification that increases the stability of the iPHK agent in a biological sample. 50. The iPHK agent according to clause 47, containing phosphorothioate or 2'-modified nucleotide. 51. The iPHK agent according to clause 47, containing at least one 5'-uridine-adenine-3 '(5'-ua-3') - a dinucleotide in which the uridine is a 2'-modified nucleotide; at least one 5'-uridine-guanine-3 '(5'-ug-3') is a dinucleotide in which 5'-uridine is a 2'-modified nucleotide; at least one 5'-cytidine-adenine-3 '(5'-ca-3') is a dinucleotide in which 5'-cytidine is a 2'-modified nucleotide; or at least one 5'-uridine-uridin-3 '(5'-uu-3') is a dinucleotide in which 5'-uridine is a 2'-modified nucleotide. 52. The iPHK agent according to claim 50, wherein said 2'-modification is selected from the group consisting of 2'-deoxy, 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-O- methoxyethyl (2'-O-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'- O-DMAP), 2'-O-dimethylamino-ethyloxyethyl (2'-O-DMAEOE) and 2'-ON-methylacetamide (2'-O-NMA). 53. The iPHK agent of claim 47, comprising a protruding nucleotide end having 1-4 unpaired nucleotides. 54. The iPHK agent of claim 53, wherein the nucleotide protruding end has 2 or 3 unpaired nucleotides. 55. The iPHK agent according to claim 53, wherein the protruding nucleotide is located at the 3 ′ end of the antisense strand of the iPHK agent. 56. An iPHK agent that inhibits the expression of the influenza A virus PB2 gene and contains a sense strand and an antisense strand, each strand containing a sequence that consists of 15-30 nucleotides that are essentially identical to SEQ ID NO: 427 and SEQ ID NO : 428, respectively, with the exception that no more than one nucleotide in each chain is replaced with another nucleotide, while the iPHK agent retains the ability to reduce the number of plaques of influenza A virus formed in the cells found in the plaque assay containing a cholesterol molecule. 57. The iPHK agent of claim 56, wherein the cholesterol molecule is conjugated to the 3 ′ end of the sense strand of the iPHK agent. 58. The iPHK agent of claim 47, wherein the iPHK agent is targeted for uptake by lung cells. 59. An iPHK agent that inhibits the expression of the influenza A virus PB2 gene and contains a sense strand and an antisense strand, each strand containing a sequence that consists of 15-30 nucleotides that are essentially identical to SEQ ID NO: 427 and SEQ ID NO : 428, respectively, with the exception that no more than one nucleotide in each strand is replaced with another nucleotide, while the iPHK agent retains the ability to reduce the number of plaques of influenza A virus formed in cells that are detected in the plaque assay containing at least one non-nucleotide single nucleotide base. 60. The iPHK agent of claim 59, wherein the unnatural nucleotide base is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. 61. The iPHK agent of claim 59, wherein the unnatural nucleotide base is difluorotolyl. 62. The iPHK agent of claim 59, wherein only one of the two oligonucleotide chains constituting the double-stranded oligonucleotide contains a non-natural nucleotide base. 63. The iPHK agent of claim 59, wherein both oligonucleotide chains constituting the double-stranded oligonucleotide independently contain a non-natural nucleotide base. 64. The iPHK agent according to clause 47, which reduces the expression of the influenza virus gene by more than 20%, 30%, 40%, 50%, 60%, 70% or 80% in cells in contact with the iPHK agent compared to cells that do not contact the iPHK agent. 65. The iPHK agent according to clause 47, which essentially retains the ability to reduce the number of plaques of influenza A virus formed in the cells found in the plaque assay. 66. The iPHK agent according to clause 47, in which the sense strand consists of the nucleotide sequence of SEQ ID NO: 427, and the antisense sequence consists of the nucleotide sequence of SEQ ID NO: 428. 67. The iPHK agent according to clause 47, containing at least one protruding nucleotide end containing two unpaired nucleotides. 68. The iPHK agent of claim 47, comprising a protruding nucleotide end at each end of the dsRNA, the protruding nucleotide end containing two unpaired nucleotides. 69. The iPHK agent according to item 47, containing at least one protruding nucleotide end containing two unpaired thymidine. 70. The use of an iPHK agent for inhibiting the expression of the PB2 gene of group A virus in an individual, where the sense strand contains 15-30 consecutive nucleotides that differ from the nucleotides of SEQ ID NO: 427 by no more than one nucleotide, and an antisense strand, where said antisense strand contains 15-30 consecutive nucleotides that differ from nucleotides of the sequence SEQ ID NO: 428 by no more than one nucleotide. 71. The application of item 70, where the specified iPHK agent is administered to the individual in an amount sufficient to reduce the level of replication of influenza virus in the cells or tissues of the specified individual. 72. The application of item 70, where the individual is a person. 73. A pharmaceutical composition for inhibiting the expression of the PB2 gene of influenza A virus, comprising:
a) iPHK agent according to any one of claims 1, 24 and 47; and
b) a pharmaceutically acceptable carrier.

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