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WO2000072022A1 - Utilisation de genes de la voie de synthese biologique du desoxy-d-xylulose phosphate - Google Patents

Utilisation de genes de la voie de synthese biologique du desoxy-d-xylulose phosphate Download PDF

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Publication number
WO2000072022A1
WO2000072022A1 PCT/EP2000/004592 EP0004592W WO0072022A1 WO 2000072022 A1 WO2000072022 A1 WO 2000072022A1 EP 0004592 W EP0004592 W EP 0004592W WO 0072022 A1 WO0072022 A1 WO 0072022A1
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WIPO (PCT)
Prior art keywords
gcpe
yfgb
protein
parasites
bacteria
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Application number
PCT/EP2000/004592
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German (de)
English (en)
Inventor
Hassan Jomaa
Original Assignee
Jomaa Pharmaka Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19923567A external-priority patent/DE19923567A1/de
Priority claimed from DE19923568A external-priority patent/DE19923568A1/de
Priority to IL14634700A priority Critical patent/IL146347A0/xx
Priority to AU50694/00A priority patent/AU5069400A/en
Priority to MXPA01011894A priority patent/MXPA01011894A/es
Priority to EA200101222A priority patent/EA200101222A1/ru
Application filed by Jomaa Pharmaka Gmbh filed Critical Jomaa Pharmaka Gmbh
Priority to CA002374608A priority patent/CA2374608A1/fr
Priority to JP2000620359A priority patent/JP2003500073A/ja
Priority to BR0011289-5A priority patent/BR0011289A/pt
Priority to EP00935082A priority patent/EP1179187A1/fr
Publication of WO2000072022A1 publication Critical patent/WO2000072022A1/fr
Priority to NO20015657A priority patent/NO20015657L/no

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation

Definitions

  • the present invention relates to the use of D ⁇ A sequences (SEQ: 1,3,5,7) which code for the gcpE or yfgB protein from bacteria or parasites and which are integrated into the genome of viruses, eukaryotes and prokaryotes change the isoprenoid content and methods for measuring the activity of the gcpE gene in relation to isoprenoid synthesis. It also relates to methods for identifying substances with herbicidal, antiparasitic, antiviral, fungicidal activity in plants and antiparasitic, antifungal and antiviral activity in humans and animals.
  • CH 2 C (CH 3 ) -CH (OH) -CH 2 -O-PO (OH) 2
  • CH 2 C (CH 3 ) -CH (OH) -CH 2 -OH
  • CH (OH) C (CH 3 ) -CH (OH) -CH 2 -O-PO (OH) 2
  • CH (OH) C (CH 3 ) -CH (OH) -CH 2 -OH, CH 3 -
  • the invention therefore relates to the use of DNA sequences which encode the gcpE or yfgB protein from bacteria or parasites from bacteria or the gcpE or yfgB protein from parasites or DNA sequences which are analogous or derivatives thereof Encode proteins in which one or more amino acids have been deleted, added or substituted by other amino acids without significantly reducing the enzymatic action of the polypeptide. It relates in particular to the use of the SEQ 1,3,5,7 DNA sequences.
  • the original origin of the specified sequences SEQ 1 and 5 and of proteins 2 and 6 is the organism Escherichia coli, strain K12.
  • the original origin of the specified sequences SEQ 3 and 7 and of proteins 4 and 8 is the organism Plasmodium Falciparum, strain 3D7.
  • sequences according to the invention are suitable for the expression of genes in viruses, eukaryytes and prokaryotes which are responsible for the isoprenoid biosynthesis of the 1-deoxy-D-xylulose pathway.
  • the eukaryotes or eukaryotic cells include animal cells, plant cells, algae, yeasts, fungi and the prokaryotes or prokaryotic bacteria are archaebacteria and eubacteria.
  • viruses, eukaryotes and prokaryotes When a DNA sequence is integrated into a genome on which one of the above-mentioned DNA sequences is located, the expression of the above-described genes in viruses, eukaryotes and prokaryotes is made possible.
  • the viruses, eukaryotes and prokaryotes transformed according to the invention are grown in a manner known per se and the isoprenoid formed in the process is isolated and, if appropriate, purified. Not all isoprenoids need to be isolated because in some cases the isoprenoids are released directly into the air.
  • the transgenic viruses, eukaryotes and prokaryotes used to change the isoprenoid content can be produced in the following steps: a) Production of a DNA sequence with the following partial sequences i) promoter which is active in viruses, eukaryotes and prokaryotes and ensures the formation of an RNA in the intended target tissue or the target cells, ii) DNA sequence which is suitable for a polypeptide with the amino acid sequence of Code gcpE or the yfgB protein from bacteria or parasites or for an analog or derivative of this polypeptide, üi) 3 'untranslated sequence which is used in viruses, eukaryotes and prokaryotes to add poly-A residues to the 3 ' end of the RNA leads, b) transfer and incorporation of the DNA sequence into the genome of viruses, prokaryotic or eukaryotic cells with or without the use of a vector (eg plasmid, viral DNA).
  • a vector eg plasmid,
  • the intact whole plants can be regenerated from the transformed plant cells.
  • sequences coding for the gcpE or the yfgB proteins or their analogs or derivatives can be provided with a promoter which ensures transcription in certain organs or cells and which is in sense orientation (3 'end of the promoter to the 5' end of the coding sequence) is coupled to the sequence encoding the protein to be formed.
  • a termination signal determining the termination of the mRNA synthesis is appended to the 3 end of the coding sequence.
  • a sequence coding for a so-called signal sequence or a transit peptide can be placed between the promoter and the coding sequence.
  • the sequence must be in the same reading frame as the coding sequence of the protein.
  • cloning vectors which contain a replication signal for E. coli and a marker which permits selection of the transformed cells. Examples of vectors are pBR 322, pUC series, M13mp series, pACYC 184, EMBL 3 etc. Depending on the method of introducing desired genes into the plant, further DNA sequences may be required.
  • the Ti or Ri plasmid is used for the transformation of the plant cell, at least one right boundary, but often the right and left boundary of the Ti and Ri plasmid T-DNA, must be inserted as the flank region of the genes to be introduced become.
  • T-DNA for the transformation of plant cells has been intensively investigated and is sufficient in EP 120516; Hoekama, in: The Binary Plant Vector System, Offset-drukkerij Kanters BV Alblasserdam (1985), Chapter V; Fraley et al., Crit.Rev.Plant Sei. 4,1-46 and An et al. (1985) EMBO J. 4, 277-287 have been described.
  • the inserted DNA is integrated in the genome, it is usually stable and is also retained in the offspring of the originally transformed cells. It normally receives a selection marker which imparts resistance to a biocide or an antibiotic, such as kanamycin, G 418, bleomycin, hygromycin or phosphinotricin and the like, to the transformed plant cells.
  • the individually used marker should therefore allow the selection of transformed cells from cells that lack the inserted DNA.
  • agrobacteria e.g. Agrobacterium tu- mefaciens
  • the fusion of protoplasts the microinjection of DNA
  • electroporation as well as ballistic methods and virus infection.
  • Whole plants can then be regenerated from transformed plant material in a suitable medium, which may contain antibiotics or biocides for selection. When it comes to injection and electroporation, there are no special requirements for the plasmids. However, if whole plants are to be regenerated from such transformed cells, the presence of a selectable marker gene is necessary.
  • the transformed cells grow within the plants in the usual way (McCormick et al. (1986), Plant Cell Reports 5, 81-84).
  • the plants can be grown normally and crossed with plants that have the same transformed genetic makeup or other genetic makeup. The resulting individuals have the corresponding phenotypic properties.
  • Expression vectors which contain one or more of the DNA sequences according to the invention are suitable for introducing the DNA into the host organisms.
  • Such expression vectors are obtained by providing the DNA sequences according to the invention with suitable functional regulatory signals.
  • Such regulatory signals are DNA sequences which are responsible for expression, for example promoters, operators, enhancers, ribosomal binding sites and which are recognized by the host organism.
  • further regulation signals which control, for example, replication or recombination of the recombinant DNA in the host organism, can be part of the expression vector.
  • Particularly suitable for the expression of the enzymes according to the invention are host cells and organisms which have no intrinsic enzymes with the function of DOXP synthase, DOXP reductoisomerase or gcpE kinase. This applies to archaebacteria, animals, fungi, slime molds and some eubacteria. The lack of these intrinsic enzyme activities makes the detection and purification of the recombinant enzymes essential facilitated. This also makes it possible to measure the activity and in particular the inhibition of the activity of the recombinant enzymes according to the invention by various chemicals and pharmaceuticals in crude extracts from the host cells with little effort.
  • the enzymes according to the invention are advantageously expressed in eukaryotic cells if post-translational modifications and a native folding of the polypeptide chain are to be achieved.
  • introns are eliminated by splicing the DNA and the enzymes are produced in the polypeptide sequence characteristic of the parasites.
  • Sequences coding for introns can also be removed by recombinant DNA technology from the DNA sequences to be expressed or inserted experimentally.
  • the protein can be isolated from the host cell or the culture supernatant of the host cell by methods known to the person skilled in the art. In vitro reactivation of the enzymes may also be required.
  • the enzymes according to the invention or partial sequences of the enzymes can be expressed as a fusion protein with various peptide chains.
  • Oligo-histidine sequences and sequences derived from glutathione-S-transferase, thioredoxin or calmodulin-binding peptides are particularly suitable for this purpose. Fusions with thioredoxin-derived sequences are particularly suitable for prokaryotic expression, since this increases the solubility of the recombinant enzymes.
  • the enzymes according to the invention or partial sequences of the enzymes can be expressed as fusion proteins with peptide chains known to those skilled in the art that the recombinant enzymes are transported into the extracellular environment or into certain compartments of the host cells. This enables both the purification and the investigation of the biological activity of the enzymes to be facilitated.
  • the enzymes according to the invention When expressing the enzymes according to the invention, it may prove expedient to change individual codons.
  • the targeted exchange of bases in the coding region also makes sense if the codons used in the parasites differ from the codon use in the heterologous expression system in order to ensure optimal synthesis of the protein.
  • deletions of untranslated 5 'or 3 'sections make sense, for example if there are several destabilizing sequence motifs ATTTA in the 3' region of the DNA. Then these should be deleted in the preferred expression in eukaryotes. Changes of this type are deletions, additions or exchange of bases and are also the subject of the present invention.
  • the enzymes according to the invention can be obtained under standardized conditions by techniques known to the person skilled in the art by in vitro translation. Suitable systems are rabbit reticulocyte and wheat germ extracts and bacterial lysates. In vitro transcribed mRNA can also be translated into Xenopus oocytes.
  • Oligo- and polypeptides can be produced by chemical synthesis, the sequences being derived from the peptide sequence of the enzymes according to the invention. With a suitable choice of the sequences, such peptides have properties which are characteristic of the complete enzymes according to the invention. Such peptides can be produced in large quantities and are particularly suitable for studies on the kinetics of enzyme activity, the regulation of enzyme activity, the three-dimensional structure of the enzymes, the inhibition of enzyme activity by different chemicals and pharmaceuticals and the binding geometry and binding affinity of different ligands.
  • Another object of this invention are methods for determining the enzymatic activity of gcpE kinase. This can be determined according to the known instructions.
  • CH 2 C (CH 3 ) -CH (OH) -CH 2 -O-PO (OH) 2
  • CH 2 (OH) -C ( CH 2 ) -C (OH) -CH 2 -OH
  • CH (OH) C (CH 3 ) -CH (OH) -CH2-O-PO (OH) 2
  • CH (OH) C (CH 3 ) -CH (OH) -CH 2 -OH
  • CH 3 - C (CH 3 ) CH-CH 2 -O-PO (OH) 2
  • CH 3 -C (CH 3 ) CH-CH 2 -OH
  • CH 2 C (CH 3 ) -CH 2 -CH 2 - O-PO (OH) 2 , detected.
  • Another object of this invention is the use of these measuring methods for the determination of substances which inhibit the activity of the respective enzymes. It has been found that the deoxy-D-xylulose-phosphate pathway is also present in many parasites, viruses and fungi.
  • the invention therefore also includes a method for screening a compound.
  • a host organism which contains a recombinant expression vector, the vector having at least a part of the oligonucleotide sequence which codes for the gcpE or the yfgB protein, or variants or homologues thereof, and also a compound which is suspected that it has an antimicrobial, antiparasitic, antiviral and antifungal activity in humans and animals or a bactericidal, antimicrobial, herbicidal or fungicidal activity in plants.
  • the host organism is then brought into contact with the compound and the effectiveness of the compound is determined.
  • the plasmid pAC-LYC was constructed according to published protocols (Cunningham, FX Jr et al., 1996, Plant Cell 8: 1613-1626).
  • the plasmid carries the genes that are required for the synthesis of the carotenoid lycopene from IPP and DMAPP.
  • E. coli cells transformed with pAC-LYC therefore form pink colonies. If the availability of the starting substances for carotenoid synthesis is increased, carotenoids are increasingly enriched and the colonies appear deep pink. An increased formation of starting substances can be achieved by overexpressing genes of the DOXP pathway.
  • the gcpe and yfgB genes from E. coli were cloned into suitable expression vectors.
  • the gcpe gene was PCR by primers 5'-CCA TGG GCC ATA ACC AGG CTC CAA TCC AA-3 'and 5'-GGA TCC TTT TTC AAC CTG CTG AAC GTC AAT-3' of genomic E. coli DNA amplified and cloned into the pCR2.1-TOPO vector.
  • the insert was cloned into the expression vector pQE60 via the restriction sites Nco I and Bam HI.
  • the yfgB gene was amplified with the primers 5'-GGA TCC ATG TCT GAA CAA TTA GTC ACA-3 'and 5'-AAG CTT TCA GAC CGC TTT AAT GTC GAT GGC-3' and in the pCRT7 / NT TOPO - vector cloned.
  • the insert was cloned into the expression vector pQE30 via the restriction cleavage Bam HI and Hind III.
  • Bacteria which had been transformed with pAC-LYC and one of the two expression constructs showed a significantly deeper staining than bacteria which, as a control, had additionally been transformed only with the empty pQE30 vector.
  • Photometric quantification of the carotenoid enrichment gave 210% for gcpe and 173% for yfgB based on the control.
  • falciparum strain 3D7 was used as a template and thermostable Pwo DNA polymerase.
  • the PCR products were phosphorylated with T4 polynucleotide kinase and cloned into pQE32 vectors that had been linearized with Sma I and dephosphorylated with alkaline phosphatase.
  • the orientation of the inserts was verified by restriction analysis.
  • the bacterial colonies obtained with these constructs showed no clear color changes.
  • photometric evaluation showed a carotenoid enrichment of 117% (gcpe) and 113% (yfgB).
  • the relatively low carotenoid accumulation with the P. falciparum genes is apparently due to the frequently observed low expression of P. falciparum genes in E. coli as a result of the high A / T content.

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Abstract

La présente invention concerne l'utilisation de séquences d'ADN provenant de bactéries et de parasites, à savoir les gènes gcpE et yfgB, pour l'intégration dans le génome de virus, d'eucaryotes et de procaryotes et, ainsi, pour la modification de la concentration d'isoprénoïde. L'invention concerne en outre un procédé permettant d'identifier des substances ayant un effet herbicide, antiparasitaire, antiviral ou fongicide chez les plantes, ainsi qu'un effet antimycotique, antiparasitaire et antiviral chez l'homme et l'animal.
PCT/EP2000/004592 1999-05-21 2000-05-20 Utilisation de genes de la voie de synthese biologique du desoxy-d-xylulose phosphate WO2000072022A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP00935082A EP1179187A1 (fr) 1999-05-21 2000-05-20 Utilisation de genes de la voie de synthese biologique du desoxy-d-xylulose phosphate
BR0011289-5A BR0011289A (pt) 1999-05-21 2000-05-20 Uso de genes das vias biossintéticas do desoxi-d-xilulose fosfato para a alteração da concentração de isoprenóide
AU50694/00A AU5069400A (en) 1999-05-21 2000-05-20 Use of genes of the deoxy-d-xylulose phosphate biosynthetic pathway for altering the concentration of isoprenoid
MXPA01011894A MXPA01011894A (es) 1999-05-21 2000-05-20 Uso de genes de las trayectorias biosinteticas de fosfato de desoxi-d-xilulosa para alterar la concentracion de isoprenoides.
EA200101222A EA200101222A1 (ru) 1999-05-21 2000-05-20 Применение генов пути биосинтеза с участием дезокси-d-ксилулоза-фосфата для изменения концентрации изопреноидов
IL14634700A IL146347A0 (en) 1999-05-21 2000-05-20 Use of genes of the deoxy-d-xylulose phosphate biosynthetic pathway for altering the concentration of isoprenoid
CA002374608A CA2374608A1 (fr) 1999-05-21 2000-05-20 Utilisation de genes de la voie de synthese biologique du desoxy-d-xylulose phosphate
JP2000620359A JP2003500073A (ja) 1999-05-21 2000-05-20 イソプレノイドの濃度を変更するためのデオキシ−ｄ−キシルロースホスフェート生合成経路の遺伝子の使用
NO20015657A NO20015657L (no) 1999-05-21 2001-11-20 Anvendelse av gener fra deoksy-D-xylulose- fosfatbiosyntesereaksjonsveien for endring av konsentrasjonen avisoprenoid

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19923568.6 1999-05-21
DE19923567.8 1999-05-21
DE19923567A DE19923567A1 (de) 1998-09-22 1999-05-21 Gene des 1-Desoxy-D-xylulose-Biosynthesewegs
DE19923568A DE19923568A1 (de) 1999-05-21 1999-05-21 Verwendung von gcp-E-Genen aus Bakterien zur Veränderung der Isoprenoidkonzentration

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PCT/EP2000/004592 WO2000072022A1 (fr) 1999-05-21 2000-05-20 Utilisation de genes de la voie de synthese biologique du desoxy-d-xylulose phosphate

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EP (1) EP1179187A1 (fr)
JP (1) JP2003500073A (fr)
CN (1) CN1351715A (fr)
AU (1) AU5069400A (fr)
BR (1) BR0011289A (fr)
CA (1) CA2374608A1 (fr)
HU (1) HUP0201386A2 (fr)
IL (1) IL146347A0 (fr)
MX (1) MXPA01011894A (fr)
NO (1) NO20015657L (fr)
PL (1) PL351756A1 (fr)
TR (1) TR200103326T2 (fr)
WO (1) WO2000072022A1 (fr)

Cited By (6)

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Publication number Priority date Publication date Assignee Title
WO2001085950A2 (fr) * 2000-05-05 2001-11-15 Jomaa Pharmaka Gmbh Genes de la voie de biosynthese 1-desoxy-d-xylulose
WO2001094561A2 (fr) * 2000-06-05 2001-12-13 Adelbert Bacher Voie isoprenoide non mevalonate
DE10119905A1 (de) * 2001-04-23 2002-10-24 Jomaa Pharmaka Gmbh Inaktivierung von Genen des MEP-Wegs
JP2005508305A (ja) * 2001-07-20 2005-03-31 バイオエージェンシー・アーゲー ガンマ／デルタｔ細胞を活性化するための有機リン化合物
US7122331B1 (en) 1999-08-04 2006-10-17 Wolfgang Eisenreich Isoprenoid biosynthesis
US7297509B2 (en) 2001-04-11 2007-11-20 Adelbert Bacher Intermediates and enzymes of the non-mevalonate isoprenoid pathway

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WO1999052938A2 (fr) * 1998-04-14 1999-10-21 Jomaa Hassan Identification de principes actifs chimiques destines a l'inhibition de la voie de biosynthese du 1-desoxy-d-xylulose-5-phosphate dans des parasites
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LOIS, LUISA MARIA ET AL: "Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of D-1-deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis", PROC. NATL. ACAD. SCI. U. S. A. (1998), 95(5), 2105-2110, XP002116673 *
SPRENGER, GEORG A. ET AL: "Identification of a thiamin-dependent synthase in Escherichia coli required for the formation of the 1-deoxy-D-xylulose 5-phosphate precursor to isoprenoids, thiamin, and pyridoxol", PROC. NATL. ACAD. SCI. U. S. A. (1997), 94(24), 12857-12862, XP002116674 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122331B1 (en) 1999-08-04 2006-10-17 Wolfgang Eisenreich Isoprenoid biosynthesis
WO2001085950A2 (fr) * 2000-05-05 2001-11-15 Jomaa Pharmaka Gmbh Genes de la voie de biosynthese 1-desoxy-d-xylulose
WO2001085950A3 (fr) * 2000-05-05 2002-06-20 Jomaa Pharmaka Gmbh Genes de la voie de biosynthese 1-desoxy-d-xylulose
WO2001094561A2 (fr) * 2000-06-05 2001-12-13 Adelbert Bacher Voie isoprenoide non mevalonate
WO2001094561A3 (fr) * 2000-06-05 2002-05-30 Adelbert Bacher Voie isoprenoide non mevalonate
US7288367B2 (en) 2000-06-05 2007-10-30 Adelbert Bacher Non-mevalonate isoprenoid pathway
US7297509B2 (en) 2001-04-11 2007-11-20 Adelbert Bacher Intermediates and enzymes of the non-mevalonate isoprenoid pathway
DE10119905A1 (de) * 2001-04-23 2002-10-24 Jomaa Pharmaka Gmbh Inaktivierung von Genen des MEP-Wegs
US7875279B2 (en) 2001-04-23 2011-01-25 Bioagency Ag Inactivation of genes of the MEP pathway
JP2005508305A (ja) * 2001-07-20 2005-03-31 バイオエージェンシー・アーゲー ガンマ／デルタｔ細胞を活性化するための有機リン化合物

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AU5069400A (en) 2000-12-12
JP2003500073A (ja) 2003-01-07
TR200103326T2 (tr) 2002-04-22
IL146347A0 (en) 2002-07-25
PL351756A1 (en) 2003-06-16
MXPA01011894A (es) 2002-06-21
BR0011289A (pt) 2002-02-26
NO20015657L (no) 2002-01-17
CA2374608A1 (fr) 2000-11-30
HUP0201386A2 (en) 2002-08-28
NO20015657D0 (no) 2001-11-20
EP1179187A1 (fr) 2002-02-13

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