CN102803492B - 通过抑制针对三重四脯氨酸(ttp)的天然反义转录物来治疗ttp相关疾病 - Google Patents
通过抑制针对三重四脯氨酸(ttp)的天然反义转录物来治疗ttp相关疾病 Download PDFInfo
- Publication number
- CN102803492B CN102803492B CN201080027720.7A CN201080027720A CN102803492B CN 102803492 B CN102803492 B CN 102803492B CN 201080027720 A CN201080027720 A CN 201080027720A CN 102803492 B CN102803492 B CN 102803492B
- Authority
- CN
- China
- Prior art keywords
- oligonucleotide
- nucleotide
- ttp
- antisense
- rna
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 28
- 201000010099 disease Diseases 0.000 title claims abstract description 27
- 108020005544 Antisense RNA Proteins 0.000 title description 18
- 230000001629 suppression Effects 0.000 title description 13
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 290
- 230000000692 anti-sense effect Effects 0.000 claims abstract description 152
- 239000000074 antisense oligonucleotide Substances 0.000 claims abstract description 76
- 238000012230 antisense oligonucleotides Methods 0.000 claims abstract description 76
- 230000014509 gene expression Effects 0.000 claims abstract description 70
- 102000040430 polynucleotide Human genes 0.000 claims abstract description 60
- 108091033319 polynucleotide Proteins 0.000 claims abstract description 60
- 239000002157 polynucleotide Substances 0.000 claims abstract description 60
- 230000008685 targeting Effects 0.000 claims abstract description 30
- 125000003729 nucleotide group Chemical group 0.000 claims description 150
- 239000002773 nucleotide Substances 0.000 claims description 138
- 150000007523 nucleic acids Chemical class 0.000 claims description 131
- 102000039446 nucleic acids Human genes 0.000 claims description 120
- 108020004707 nucleic acids Proteins 0.000 claims description 120
- 108090000623 proteins and genes Proteins 0.000 claims description 86
- 239000002253 acid Substances 0.000 claims description 57
- -1 phosphonate ester Chemical class 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 40
- 230000004048 modification Effects 0.000 claims description 29
- 238000012986 modification Methods 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 25
- 239000002777 nucleoside Substances 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 22
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 108091093037 Peptide nucleic acid Proteins 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 15
- 241001597008 Nomeidae Species 0.000 claims description 14
- 238000001727 in vivo Methods 0.000 claims description 14
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 201000011510 cancer Diseases 0.000 claims description 13
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 239000010452 phosphate Substances 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 8
- 239000011574 phosphorus Substances 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 7
- 235000015177 dried meat Nutrition 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 230000003827 upregulation Effects 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims description 5
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 2
- 238000005034 decoration Methods 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 2
- JKPAIQYTAZUMKI-UHFFFAOYSA-N N[P] Chemical compound N[P] JKPAIQYTAZUMKI-UHFFFAOYSA-N 0.000 claims 1
- HPXRVTGHNJAIIH-PTQBSOBMSA-N cyclohexanol Chemical group O[13CH]1CCCCC1 HPXRVTGHNJAIIH-PTQBSOBMSA-N 0.000 claims 1
- 229930182470 glycoside Natural products 0.000 claims 1
- 150000002338 glycosides Chemical class 0.000 claims 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 abstract description 7
- 238000012797 qualification Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 149
- 229920002477 rna polymer Polymers 0.000 description 134
- 108020004414 DNA Proteins 0.000 description 79
- 102000053602 DNA Human genes 0.000 description 77
- 238000000034 method Methods 0.000 description 64
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 60
- 108020004999 messenger RNA Proteins 0.000 description 58
- 239000002585 base Substances 0.000 description 55
- 210000004027 cell Anatomy 0.000 description 53
- 230000006870 function Effects 0.000 description 52
- 230000000295 complement effect Effects 0.000 description 44
- 230000000694 effects Effects 0.000 description 35
- 108020004459 Small interfering RNA Proteins 0.000 description 32
- 230000033228 biological regulation Effects 0.000 description 31
- 238000011282 treatment Methods 0.000 description 26
- 238000009396 hybridization Methods 0.000 description 25
- 210000001519 tissue Anatomy 0.000 description 25
- 239000002502 liposome Substances 0.000 description 24
- 239000000523 sample Substances 0.000 description 24
- 238000005520 cutting process Methods 0.000 description 23
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 21
- 230000002255 enzymatic effect Effects 0.000 description 20
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 19
- 108091081024 Start codon Proteins 0.000 description 19
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- 108090000994 Catalytic RNA Proteins 0.000 description 17
- 102000053642 Catalytic RNA Human genes 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- 108091092562 ribozyme Proteins 0.000 description 17
- 230000008859 change Effects 0.000 description 16
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- 241000894007 species Species 0.000 description 15
- 230000014616 translation Effects 0.000 description 15
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 14
- 150000002632 lipids Chemical group 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 102100031622 mRNA decay activator protein ZFP36 Human genes 0.000 description 13
- 230000014621 translational initiation Effects 0.000 description 13
- 229930024421 Adenine Natural products 0.000 description 12
- 108020005038 Terminator Codon Proteins 0.000 description 12
- 241000218636 Thuja Species 0.000 description 12
- 229960000643 adenine Drugs 0.000 description 12
- 239000000039 congener Substances 0.000 description 12
- 230000002969 morbid Effects 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 238000013519 translation Methods 0.000 description 12
- 239000013598 vector Substances 0.000 description 12
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 11
- 108091026890 Coding region Proteins 0.000 description 11
- 230000027455 binding Effects 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 238000011160 research Methods 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 101710163270 Nuclease Proteins 0.000 description 10
- 238000013461 design Methods 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 239000000178 monomer Substances 0.000 description 10
- 230000002441 reversible effect Effects 0.000 description 10
- RYVNIFSIEDRLSJ-UHFFFAOYSA-N 5-(hydroxymethyl)cytosine Chemical compound NC=1NC(=O)N=CC=1CO RYVNIFSIEDRLSJ-UHFFFAOYSA-N 0.000 description 9
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 9
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 230000008499 blood brain barrier function Effects 0.000 description 9
- 210000001218 blood-brain barrier Anatomy 0.000 description 9
- 235000012000 cholesterol Nutrition 0.000 description 9
- 239000003184 complementary RNA Substances 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 238000003752 polymerase chain reaction Methods 0.000 description 9
- 108700028369 Alleles Proteins 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 229940104302 cytosine Drugs 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 108091027963 non-coding RNA Proteins 0.000 description 8
- 102000042567 non-coding RNA Human genes 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 8
- 210000001541 thymus gland Anatomy 0.000 description 8
- 239000013603 viral vector Substances 0.000 description 8
- 108020004705 Codon Proteins 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 230000002708 enhancing effect Effects 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000003961 penetration enhancing agent Substances 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 241000701161 unidentified adenovirus Species 0.000 description 7
- 229940035893 uracil Drugs 0.000 description 7
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 6
- 108020004635 Complementary DNA Proteins 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- 239000013614 RNA sample Substances 0.000 description 6
- 108091029810 SaRNA Proteins 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 210000002216 heart Anatomy 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 108091070501 miRNA Proteins 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 238000003753 real-time PCR Methods 0.000 description 6
- 229940078677 sarna Drugs 0.000 description 6
- 239000004055 small Interfering RNA Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- 101000795753 Homo sapiens mRNA decay activator protein ZFP36 Proteins 0.000 description 5
- 102100034343 Integrase Human genes 0.000 description 5
- 101710203526 Integrase Proteins 0.000 description 5
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 5
- 108091092724 Noncoding DNA Proteins 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 108700008625 Reporter Genes Proteins 0.000 description 5
- 238000002105 Southern blotting Methods 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 150000001413 amino acids Chemical group 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 230000003321 amplification Effects 0.000 description 5
- 230000004700 cellular uptake Effects 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 229960000485 methotrexate Drugs 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- 230000003285 pharmacodynamic effect Effects 0.000 description 5
- 229920000768 polyamine Polymers 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 238000004088 simulation Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- LPXQRXLUHJKZIE-UHFFFAOYSA-N 8-azaguanine Chemical compound NC1=NC(O)=C2NN=NC2=N1 LPXQRXLUHJKZIE-UHFFFAOYSA-N 0.000 description 4
- 230000004543 DNA replication Effects 0.000 description 4
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 239000004952 Polyamide Substances 0.000 description 4
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 4
- 108091027967 Small hairpin RNA Proteins 0.000 description 4
- 108091060271 Small temporal RNA Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 108010065850 Tristetraprolin Proteins 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- 238000010306 acid treatment Methods 0.000 description 4
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000009368 gene silencing by RNA Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000138 intercalating agent Substances 0.000 description 4
- 230000002452 interceptive effect Effects 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 208000010125 myocardial infarction Diseases 0.000 description 4
- 230000009871 nonspecific binding Effects 0.000 description 4
- 238000006384 oligomerization reaction Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 230000004962 physiological condition Effects 0.000 description 4
- 230000008488 polyadenylation Effects 0.000 description 4
- 229920002647 polyamide Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 230000009870 specific binding Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 3
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 3
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 239000004380 Cholic acid Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102100031780 Endonuclease Human genes 0.000 description 3
- 108010042407 Endonucleases Proteins 0.000 description 3
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 208000009525 Myocarditis Diseases 0.000 description 3
- 108700026244 Open Reading Frames Proteins 0.000 description 3
- 229910052770 Uranium Inorganic materials 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000003613 bile acid Substances 0.000 description 3
- 239000003833 bile salt Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 3
- 235000019416 cholic acid Nutrition 0.000 description 3
- 229960002471 cholic acid Drugs 0.000 description 3
- 238000004590 computer program Methods 0.000 description 3
- 239000005289 controlled pore glass Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- GTZOYNFRVVHLDZ-UHFFFAOYSA-N dodecane-1,1-diol Chemical group CCCCCCCCCCCC(O)O GTZOYNFRVVHLDZ-UHFFFAOYSA-N 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 238000010195 expression analysis Methods 0.000 description 3
- 238000001502 gel electrophoresis Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
- 210000002161 motor neuron Anatomy 0.000 description 3
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 150000004713 phosphodiesters Chemical group 0.000 description 3
- 229920000151 polyglycol Polymers 0.000 description 3
- 239000010695 polyglycol Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 208000037816 tissue injury Diseases 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229940075420 xanthine Drugs 0.000 description 3
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 2
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-amino-7-methyl-1,7-dihydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 2
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 2
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical compound CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- HCGHYQLFMPXSDU-UHFFFAOYSA-N 7-methyladenine Chemical compound C1=NC(N)=C2N(C)C=NC2=N1 HCGHYQLFMPXSDU-UHFFFAOYSA-N 0.000 description 2
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 description 2
- 108020004491 Antisense DNA Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 101000672034 Bacillus sp. (strain GL1) Unsaturated glucuronyl hydrolase Proteins 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 2
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 2
- 108020004394 Complementary RNA Proteins 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 description 2
- 108091060211 Expressed sequence tag Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 108090001102 Hammerhead ribozyme Proteins 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 229930010555 Inosine Natural products 0.000 description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 2
- 241000270322 Lepidosauria Species 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 206010028594 Myocardial fibrosis Diseases 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 229910004679 ONO2 Inorganic materials 0.000 description 2
- 206010033649 Pancreatitis chronic Diseases 0.000 description 2
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 108700005075 Regulator Genes Proteins 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 108091036066 Three prime untranslated region Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine group Chemical group [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12 OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 125000005122 aminoalkylamino group Chemical group 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 239000003816 antisense DNA Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 125000005340 bisphosphate group Chemical group 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 201000001352 cholecystitis Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 108010082025 cyan fluorescent protein Proteins 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229960003786 inosine Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- DRAVOWXCEBXPTN-UHFFFAOYSA-N isoguanine Chemical compound NC1=NC(=O)NC2=C1NC=N2 DRAVOWXCEBXPTN-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 208000012804 lymphangiosarcoma Diseases 0.000 description 2
- 101710098598 mRNA decay activator protein ZFP36 Proteins 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 108010058731 nopaline synthase Proteins 0.000 description 2
- 238000003499 nucleic acid array Methods 0.000 description 2
- 238000007899 nucleic acid hybridization Methods 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 201000010198 papillary carcinoma Diseases 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 2
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 108010054624 red fluorescent protein Proteins 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 230000003362 replicative effect Effects 0.000 description 2
- 125000006853 reporter group Chemical group 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- YLWAQARRNQVEHD-PBZHRCKQSA-N tazettine Chemical compound O([C@]1(O)CN2C)CC3=CC=4OCOC=4C=C3[C@]31[C@@H]2C[C@H](OC)C=C3 YLWAQARRNQVEHD-PBZHRCKQSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- ZEMGGZBWXRYJHK-UHFFFAOYSA-N thiouracil Chemical compound O=C1C=CNC(=S)N1 ZEMGGZBWXRYJHK-UHFFFAOYSA-N 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000017105 transposition Effects 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- YIMATHOGWXZHFX-WCTZXXKLSA-N (2r,3r,4r,5r)-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolane-2,4-diol Chemical compound COCCO[C@H]1[C@H](O)O[C@H](CO)[C@H]1O YIMATHOGWXZHFX-WCTZXXKLSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- OREKERSNHHDONJ-QHCPKHFHSA-N (2s)-n-[4-(benzimidazol-1-yl)-2-fluorophenyl]-2-(5-carbamimidoyl-1h-indol-3-yl)-3-phenylpropanamide Chemical compound C([C@@H](C1=CNC2=CC=C(C=C21)C(=N)N)C(=O)NC=1C(=CC(=CC=1)N1C2=CC=CC=C2N=C1)F)C1=CC=CC=C1 OREKERSNHHDONJ-QHCPKHFHSA-N 0.000 description 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- ZMZGFLUUZLELNE-UHFFFAOYSA-N 2,3,5-triiodobenzoic acid Chemical compound OC(=O)C1=CC(I)=CC(I)=C1I ZMZGFLUUZLELNE-UHFFFAOYSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical group NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- QSHACTSJHMKXTE-UHFFFAOYSA-N 2-(2-aminopropyl)-7h-purin-6-amine Chemical compound CC(N)CC1=NC(N)=C2NC=NC2=N1 QSHACTSJHMKXTE-UHFFFAOYSA-N 0.000 description 1
- PBUUPFTVAPUWDE-UGZDLDLSSA-N 2-[[(2S,4S)-2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2lambda5-oxazaphosphinan-4-yl]sulfanyl]ethanesulfonic acid Chemical compound OS(=O)(=O)CCS[C@H]1CCO[P@](=O)(N(CCCl)CCCl)N1 PBUUPFTVAPUWDE-UGZDLDLSSA-N 0.000 description 1
- BRLJKBOXIVONAG-UHFFFAOYSA-N 2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(O)=O BRLJKBOXIVONAG-UHFFFAOYSA-N 0.000 description 1
- CVOFKRWYWCSDMA-UHFFFAOYSA-N 2-chloro-n-(2,6-diethylphenyl)-n-(methoxymethyl)acetamide;2,6-dinitro-n,n-dipropyl-4-(trifluoromethyl)aniline Chemical compound CCC1=CC=CC(CC)=C1N(COC)C(=O)CCl.CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O CVOFKRWYWCSDMA-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- XIFVTSIIYVGRHJ-UHFFFAOYSA-N 2-n,2-n,4-n,4-n,6-n-pentamethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N(C)C)=NC(N(C)C)=N1 XIFVTSIIYVGRHJ-UHFFFAOYSA-N 0.000 description 1
- YNFSUOFXEVCDTC-UHFFFAOYSA-N 2-n-methyl-7h-purine-2,6-diamine Chemical compound CNC1=NC(N)=C2NC=NC2=N1 YNFSUOFXEVCDTC-UHFFFAOYSA-N 0.000 description 1
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- OVONXEQGWXGFJD-UHFFFAOYSA-N 4-sulfanylidene-1h-pyrimidin-2-one Chemical compound SC=1C=CNC(=O)N=1 OVONXEQGWXGFJD-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- PLUDYDNNASPOEE-UHFFFAOYSA-N 6-(aziridin-1-yl)-1h-pyrimidin-2-one Chemical compound C1=CNC(=O)N=C1N1CC1 PLUDYDNNASPOEE-UHFFFAOYSA-N 0.000 description 1
- SXQMWXNOYLLRBY-UHFFFAOYSA-N 6-(methylamino)purin-8-one Chemical compound CNC1=NC=NC2=NC(=O)N=C12 SXQMWXNOYLLRBY-UHFFFAOYSA-N 0.000 description 1
- QNNARSZPGNJZIX-UHFFFAOYSA-N 6-amino-5-prop-1-ynyl-1h-pyrimidin-2-one Chemical compound CC#CC1=CNC(=O)N=C1N QNNARSZPGNJZIX-UHFFFAOYSA-N 0.000 description 1
- CKOMXBHMKXXTNW-UHFFFAOYSA-N 6-methyladenine Chemical group CNC1=NC=NC2=C1N=CN2 CKOMXBHMKXXTNW-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical compound NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 108010000700 Acetolactate synthase Proteins 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000000197 Acute Cholecystitis Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 241000282979 Alces alces Species 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 108010032595 Antibody Binding Sites Proteins 0.000 description 1
- 241000239290 Araneae Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000796533 Arna Species 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 101150010856 CRT gene Proteins 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 206010008614 Cholecystitis acute Diseases 0.000 description 1
- 206010008617 Cholecystitis chronic Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N D-Maltose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-Threitol Natural products OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- SHZGCJCMOBCMKK-SVZMEOIVSA-N D-fucopyranose Chemical compound C[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O SHZGCJCMOBCMKK-SVZMEOIVSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- SRBFZHDQGSBBOR-AGQMPKSLSA-N D-lyxopyranose Chemical compound O[C@@H]1COC(O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-AGQMPKSLSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 101100476962 Drosophila melanogaster Sirup gene Proteins 0.000 description 1
- 239000012594 Earle’s Balanced Salt Solution Substances 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 241000700662 Fowlpox virus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 108010070875 Human Immunodeficiency Virus tat Gene Products Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 208000029549 Muscle injury Diseases 0.000 description 1
- 241001508687 Mustela erminea Species 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- PYUSHNKNPOHWEZ-YFKPBYRVSA-N N-formyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC=O PYUSHNKNPOHWEZ-YFKPBYRVSA-N 0.000 description 1
- 206010051606 Necrotising colitis Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- AYRXSINWFIIFAE-UHFFFAOYSA-N O6-alpha-D-Galactopyranosyl-D-galactose Natural products OCC1OC(OCC(O)C(O)C(O)C(O)C=O)C(O)C(O)C1O AYRXSINWFIIFAE-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 241000282943 Odocoileus Species 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N Phosphinothricin Natural products CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101710149951 Protein Tat Proteins 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 206010037601 Pyelonephritis chronic Diseases 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 101710086015 RNA ligase Proteins 0.000 description 1
- 230000007022 RNA scission Effects 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- XEEPVFFWNATEGX-IUHNQTRMSA-N Tazettadiol Natural products C1=C(CO)C([C@]23[C@H](O)CN(C)[C@H]2C[C@@H](C=C3)OC)=CC2=C1OCO2 XEEPVFFWNATEGX-IUHNQTRMSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000002070 Transferrins Human genes 0.000 description 1
- 108010015865 Transferrins Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000282485 Vulpes vulpes Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- RLXCFCYWFYXTON-JTTSDREOSA-N [(3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl] N-hexylcarbamate Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(OC(=O)NCCCCCC)[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 RLXCFCYWFYXTON-JTTSDREOSA-N 0.000 description 1
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 201000010442 acute cervicitis Diseases 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- PYMYPHUHKUWMLA-VAYJURFESA-N aldehydo-L-arabinose Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-VAYJURFESA-N 0.000 description 1
- PNNNRSAQSRJVSB-KCDKBNATSA-N aldehydo-L-fucose Chemical compound C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-KCDKBNATSA-N 0.000 description 1
- PYMYPHUHKUWMLA-YUPRTTJUSA-N aldehydo-L-lyxose Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-YUPRTTJUSA-N 0.000 description 1
- 125000002009 alkene group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-MBMOQRBOSA-N alpha-D-arabinopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@@H]1O SRBFZHDQGSBBOR-MBMOQRBOSA-N 0.000 description 1
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 101150036080 at gene Proteins 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical compound C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 206010007625 cardiogenic shock Diseases 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 201000003988 chronic cervicitis Diseases 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 201000006368 chronic pyelonephritis Diseases 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 108700007153 dansylsarcosine Proteins 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- VUSHQLWDOJFSGF-UHFFFAOYSA-L disodium 3-carboxy-3,5-dihydroxy-5-oxopentanoate chloride Chemical compound [Na+].[Na+].Cl.[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O VUSHQLWDOJFSGF-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 201000009274 endometriosis of uterus Diseases 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 210000001353 entorhinal cortex Anatomy 0.000 description 1
- 108700004025 env Genes Proteins 0.000 description 1
- 101150030339 env gene Proteins 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 208000002854 epidermolysis bullosa simplex superficialis Diseases 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- DLKYYJFLRUUGHJ-SSJCJZGYSA-A fomivirsen sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([S-])(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DLKYYJFLRUUGHJ-SSJCJZGYSA-A 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108700004026 gag Genes Proteins 0.000 description 1
- 101150098622 gag gene Proteins 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000003633 gene expression assay Methods 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- DLRVVLDZNNYCBX-CQUJWQHSSA-N gentiobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)C(O)O1 DLRVVLDZNNYCBX-CQUJWQHSSA-N 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- IAJOBQBIJHVGMQ-BYPYZUCNSA-N glufosinate-P Chemical compound CP(O)(=O)CC[C@H](N)C(O)=O IAJOBQBIJHVGMQ-BYPYZUCNSA-N 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010842 high-capacity cDNA reverse transcription kit Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960002899 hydroxyprogesterone Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 239000008206 lipophilic material Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229950000547 mafosfamide Drugs 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 210000002433 mononuclear leukocyte Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 210000003887 myelocyte Anatomy 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000003757 neuroblast Anatomy 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 150000005053 phenanthridines Chemical class 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229940061584 phosphoramidic acid Drugs 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 101150088264 pol gene Proteins 0.000 description 1
- 229920001197 polyacetylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- KLJOYDMUWKSYBP-SLEMLFNQSA-N pretazettine Natural products CO[C@H]1C[C@@H]2N(C)C[C@@H]3O[C@@H](O)c4cc5OCOc5cc4[C@]23C=C1 KLJOYDMUWKSYBP-SLEMLFNQSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000003498 protein array Methods 0.000 description 1
- 239000002423 protozoacide Substances 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- YLWAQARRNQVEHD-UHFFFAOYSA-N sekisanoline Natural products CN1CC2(O)OCC3=CC=4OCOC=4C=C3C32C1CC(OC)C=C3 YLWAQARRNQVEHD-UHFFFAOYSA-N 0.000 description 1
- JRPHGDYSKGJTKZ-UHFFFAOYSA-K selenophosphate Chemical compound [O-]P([O-])([O-])=[Se] JRPHGDYSKGJTKZ-UHFFFAOYSA-K 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 101150012509 sub gene Proteins 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical group NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 230000003582 thrombocytopenic effect Effects 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-O trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=[NH+]C(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-O 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
Classifications
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/313—Phosphorodithioates
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/314—Phosphoramidates
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/321—2'-O-R Modification
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/322—2'-R Modification
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
- C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Analytical Chemistry (AREA)
- Plant Pathology (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Virology (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
本发明涉及反义寡核苷酸,具体而言,其通过靶向三重四脯氨酸(TTP)的天然反义多核苷酸,调节三重四脯氨酸(TTP)的表达和/或功能。本发明还涉及这些反义寡核苷酸的鉴定及其在治疗与TTP表达有关的疾病和病症中的用途。
Description
技术领域
本申请要求提交于2009年5月6日的美国临时专利申请第61/175,812号的优先权,其通过引用全部并入本文。
本发明的实施方案包括调节TTP和相关分子的表达和/或功能的寡核苷酸。
背景技术
DNA-RNA和RNA-RNA杂交对于核酸功能的许多方面(包括DNA复制、转录和翻译)而言为重要的。杂交对于探测特定核酸或者改变其表达的各种技术而言亦为主要的。反义核苷酸例如通过与靶RNA杂交来扰乱基因表达,从而干扰RNA剪接、转录、翻译和复制。反义DNA具有附加的特征,该特征为DNA-RNA杂合体充当核糖核酸酶H消化的底物,该活性存在于大多数细胞类型中。可将反义分子递送到细胞中,这与寡脱氧核苷酸(ODN)的情况一样,或者它们如RNA分子一样可由内源基因表达。FDA最近批准了一种反义药物,VITRAVENE (用于治疗巨细胞病毒视网膜炎),这反映了反义物具有治疗应用。
发明概述
提供本概述以呈现本发明的概述,从而简要地指出本发明的性质和实质。在理解以下的情况下提出本概述:其不会用于解释或限制权利要求的范围或含义。
在一个实施方案中,本发明提供通过使用靶向天然反义转录物的任何区域的反义寡核苷酸来抑制天然反义转录物的作用,引起相应有义基因的增量调节的方法。本文也考虑天然反义转录物的抑制可通过siRNA、核酶和小分子来达到,认为所述siRNA、核酶和小分子在本发明的范围之内。
一个实施方案提供在体内或体外调节患者细胞或组织中的TTP(Tristetraproline)多核苷酸的功能和/或表达的方法,所述方法包括用长度为5-30个核苷酸的反义寡核苷酸接触所述细胞或组织,其中所述寡核苷酸与以下多核苷酸的反向互补序列具有至少50%的序列同一性,所述多核苷酸包含在SEQ ID NO: 3的核苷酸1-970、SEQID NO: 4的核苷酸1-1117 和SEQ ID NO: 5的核苷酸1-297(图3) 之内的5-30个连续核苷酸;从而在体内或体外调节患者细胞或组织中的TTP多核苷酸的功能和/或表达。
在另一个优选的实施方案中,寡核苷酸靶向TTP多核苷酸的天然反义序列,例如SEQ ID NO: 3-5所述的核苷酸,以及其任何变体、等位基因、同源物、突变体、衍生物、片段和互补序列。反义寡核苷酸的实例如SEQ ID NO: 6-10 (图4)所述。
另一个实施方案提供在体内或体外调节患者细胞或组织中TTP多核苷酸的功能和/或表达的方法,所述方法包括用长度为5-30个核苷酸的反义寡核苷酸接触所述细胞或组织,其中所述寡核苷酸与TTP多核苷酸的反义物的反向互补序列具有至少50%的序列同一性;从而在体内或体外调节患者细胞或组织中TTP多核苷酸的功能和/或表达。
另一个实施方案提供在体内或体外调节患者细胞或组织中TTP多核苷酸的功能和/或表达的方法,所述方法包括用长度为5-30个核苷酸的反义寡核苷酸接触所述细胞或组织,其中所述寡核苷酸与TTP反义多核苷酸的反义寡核苷酸具有至少50%的序列同一性;从而在体内或体外调节患者细胞或组织中TTP多核苷酸的功能和/或表达。
在优选的实施方案中,组合物包含一种或多种与有义和/或反义TTP多核苷酸结合的反义寡核苷酸。
在另一个优选的实施方案中,所述寡核苷酸包含一个或多个经修饰或取代的核苷酸。
在另一个优选的实施方案中,所述寡核苷酸包含一个或多个经修饰的键。
在又一个实施方案中,所述修饰核苷酸包含经修饰的碱基,该碱基包含硫代磷酸酯、甲基膦酸酯、肽核酸、2’-O-甲基、氟或碳、亚甲基或其他锁定核酸(LNA)分子。优选地,所述修饰核苷酸为锁定核酸分子,包括α-L-LNA。
在另一个优选的实施方案中,将所述寡核苷酸经皮下、肌内、静脉内或腹膜内给予患者。
在另一个优选的实施方案中,将所述寡核苷酸在药物组合物中给予。治疗方案包括至少一次向患者给予反义化合物;然而,可将此治疗修改成在一段时间内包含多次给药。所述治疗可与一种或多种其它类型的疗法组合。
在另一个优选的实施方案中,将所述寡核苷酸封装到脂质体中或附着于载体分子(例如胆固醇、TAT肽)。
其它方面描述于下文。
附图简述
图1:
图1为实时PCR结果的图表,显示相比于对照,用硫代磷酸寡核苷酸处理HepG2细胞后TTP mRNA的倍数变化+标准偏差,所述硫代磷酸寡核苷酸使用Lipofectamine 2000引入。实时PCR结果显示HepG2细胞中TTP mRNA水平在用针对TTP反义物Hs.702367设计的siRNA中的两种(CUR-0370和CUR-0372)、针对TTP反义物AL513578设计的两种siRNA (CUR-0368和CUR-0336)和针对BG012178 设计的一种siRNA (CUR-0364)处理后48 h显著增加。表示为CUR-0364、CUR-0366和CUR-0368、CUR-0370和CUR-0372的条分别对应用SEQ ID NO: 6-10处理的样品。
图2显示
SEQ ID NO: 1:智人锌指蛋白36,C3H型 (小鼠)( ZFP36) mRNA。(NCBI登记号:NM_003407)。
SEQ ID NO: 2:TTP的基因组序列(外显子用大写字母显示,内含子用小写字母显示)。
图3显示
SEQ ID NO: 3:天然TTP反义序列(Hs.702367)
SEQ ID NO: 4: 天然TTP反义序列(AL513578)
SEQ ID NO: 5: 天然TTP反义序列(BG012178)。
图4显示反义寡核苷酸SEQ ID NO: 6-10。‘r’指RNA。
图5显示有义寡核苷酸SEQ ID NO: 11-15。有义寡核苷酸SEQ ID NO: 11-15分别为反义寡核苷酸SEQ ID NO: 6-10的反向互补序列。‘r’指RNA。
发明详述
参考用于说明的示例应用在下文中描述本发明的数个方面。应当理解的是,陈述许多具体细节、关系和方法来提供对本发明的充分理解。然而,在相关领域的普通技术人员将容易地认识到,可在不含一个或多个具体细节的情况下实施本发明或者可用其他方法来实施本发明。本发明不受行为或事件的排序限制,因为一些行为可以不同的顺序进行和/或与其他行为或事件同时进行。此外,并非所有说明性的行为或事件对实施本发明的方法都为必需的。
本文公开的所有基因、基因名称和基因产物意图对应来自任何物种的同源物,对该物种而言本文公开的组合物和方法为适用的。因此,该术语包括但不限于来自人和小鼠的基因和基因产物。理解的是,当公开来自具体物种的基因或基因产物时,意图此公开仅为示范性的,并且除非其出现的文段中明确指示,否则不应理解为限制。因此,例如,对于本文公开的在一些实施方案中有关哺乳动物核酸和氨基酸序列的基因而言,意图包括来自其他动物(包括但不限于其他哺乳动物、鱼类、两栖动物、爬行动物和鸟类)的同源和/或直向同源基因和基因产物。在优选的实施方案中,所述基因或核酸序列为人的。
定义
本文所用的术语仅以描述具体的实施方案为目的而不意图限制本发明。除非文段另有明确指示,否则本文所用的单数形式“一”、“一个”和“所述”也意图包括复数形式。此外,就术语“包括的”、“包括”、“具有的”、“具有”、“含有”或其变型在详述和/或权利要求中所用的程度而言,这类术语意图以类似于术语“包含”的方式是包括在内的。
术语“约”或“大约”意为在由本领域普通技术人员所确定的具体值的可接受误差范围之内,这部分取决于该值是如何测定或确定的,即,测量系统的限制。例如,按照本领域的实践,“约”可意为在1之内或大于1的标准偏差。或者,“约”可意为高达给定值的20%,优选10%,更优选5%,和还更优选1%的范围。或者,具体地关于生物系统或过程,该术语可意为在值的数量级之内,优选在值的5倍之内,更优选在2倍之内。当本申请和权利要求描述具体值时,除非另作说明,否则应假设术语“约”意为在具体值的可接受误差范围之内。
本文所用的术语“mRNA”意为目前已知的靶向基因的mRNA转录物,以及任何可阐明的其它转录物。
“反义寡核苷酸”或“反义化合物”意为与另一个RNA或DNA(靶RNA、DNA)结合的RNA或DNA分子。例如,如果其为RNA寡核苷酸,则其通过RNA-RNA相互作用结合另一个RNA靶标并改变靶RNA的活性(Eguchi等, (1991) Ann. Rev. Biochem. 60, 631-652)。反义寡核苷酸可增量调节或减量调节特定多核苷酸的表达和/或功能。该定义意在包括从治疗、诊断或其他观点来看有用的任何外源RNA或DNA分子。这类分子包括例如反义RNA或DNA分子、干扰RNA(RNAi)、微小RNA、诱饵RNA分子、siRNA、酶促RNA、治疗用编辑RNA (therapeutic editingRNA)以及激动剂和拮抗剂RNA、反义寡聚化合物、反义寡核苷酸、外部指导序列(EGS)寡核苷酸、可变剪接物(alternate splicer)、引物、探针以及其他与靶核酸的至少一部分杂交的寡聚化合物。因此,可将这些化合物以单链、双链、部分单链或环状寡聚化合物的形式引入。
在本发明的文段中,术语“寡核苷酸”是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其模拟物的寡聚物或聚合物。术语“寡核苷酸”,也包括天然和/或经修饰单体或键(linkage)的线性或环状寡聚体,包括脱氧核糖核苷、核糖核苷、其取代和α-异头物形式、肽核酸(PNA)、锁定核酸(LNA)、硫代磷酸酯、甲基膦酸酯等。寡核苷酸能够通过单体与单体相互作用的规律模式(例如沃森-克里克(Watson-Crick)型碱基配对、Hoögsteen或反Hoögsteen型碱基配对等)特异地结合靶多核苷酸。
寡核苷酸可为“嵌合的”,即,由不同的区组成。在本发明的文段中,“嵌合的”化合物为寡核苷酸,其包含两个或更多个化学区,例如,DNA区、RNA区、PNA区等。每个化学区由至少一个单体单元(即,在寡核苷酸化合物的情况下为核苷酸)组成。这些寡核苷酸典型地包含至少一个区,其中所述寡核苷酸为经修饰的以表现出一种或多种所需特性。寡核苷酸的所需特性包括但不限于,例如增强的对核酸酶降解的抗性、增强的细胞摄取和/或增强的对靶核酸的结合亲和力。因此寡核苷酸的不同区可具有不同的特性。本发明的嵌合寡核苷酸可形成为两种或更多种如上所述的寡核苷酸、修饰寡核苷酸、寡聚核苷和/或寡核苷酸类似物的混合结构。
寡核苷酸可由可“全符合状态(in “register”)”地连接或通过间隔物连接的区组成,所述“全符合状态”地连接即此时单体像在天然DNA一样连续地连接。所述间隔物意在构成区之间的共价“桥”,并在优选的情况下具有不超过约100个碳原子的长度。所述间隔物可携带不同的功能性,例如具有正或负电荷的、具有特殊的核酸结合特性(嵌入剂、沟黏合剂、毒素、荧光团等)、为亲脂的、诱导特殊的二级结构如例如诱导α-螺旋的含丙氨酸的肽。
本文所用的“TTP”和“三重四脯氨酸”包括所有家族成员、突变体、等位基因、片段、种类(species)、编码和非编码序列、有义和反义多核苷酸链等。
本文所用的措词“三重四脯氨酸”、TTP、‘锌指蛋白36同源物’, ‘锌指蛋白36’、Zfp-36、ZFP36和G0S24、GOS24、TIS11、生长因子诱导型核蛋白NUP475和GO/Gl开关调节蛋白24、NUP475和RNF162A在本申请中可交换地使用。
本文所用的术语“对……特异的寡核苷酸”或“靶向……的寡核苷酸”是指具有以下序列的寡核苷酸,该序列(i)能够与靶向基因的一部分形成稳定的复合体,或(ii)能够与靶向基因的mRNA转录物的一部分形成稳定的双链体。复合体和双链体的稳定性可通过理论计算和/或体外测定来确定。用于确定杂交复合体和双链体的稳定性的示例性测定法描述于下文实施例中。
本文所用的术语“靶核酸”包括DNA、从这类DNA转录的RNA (包括前mRNA和mRNA),以及从这类RNA衍生的cDNA、编码序列、非编码序列、有义或反义多核苷酸。寡聚化合物与其靶核酸的特异性杂交干扰核酸的正常功能。这种通过特异地与靶核酸杂交的化合物对该靶核酸功能的调节,一般称为“反义”。待干扰的DNA功能包括例如复制和转录。待干扰的RNA功能,包括所有的生活机能,例如,RNA向蛋白质翻译位点的易位、蛋白质自RNA的翻译、产生一种或多种mRNA种类的RNA剪接,以及可由RNA参与或促进的催化活性。对靶核酸功能的这类干扰的整体效果为对编码产物或寡核苷酸表达的调节。
RNA干扰“RNAi”由双链RNA(dsRNA)分子介导,该分子具有与其“靶”核酸序列的序列特异性同源性(Caplen, N. J.等,(2001) Proc. Natl. Acad. Sci. USA 98:9742-9747)。在本发明的某些实施方案中,介体为5-25个核苷酸的“小干扰”RNA双链体(siRNA)。siRNA通过称为切酶的RNA酶对dsRNA的加工得到(Bernstein, E.等,(2001) Nature 409:363-366)。siRNA双链体产物被募集到叫做RISC (RNA诱导的沉默复合体)的多蛋白siRNA复合体中。不希望受任何具体理论所约束,认为随后RISC被引向靶核酸(适当地为mRNA),其中siRNA双链体以序列特异性的方式相互作用来介导催化方式的切割(Bernstein, E.等,(2001) Nature 409:363-366;Boutla, A.等,(2001) Curr. Biol. 11:1776-1780)。可依照本发明使用的小干扰RNA,可根据本领域众所周知和普通技术人员熟悉的程序来合成和使用。用于本发明的方法中的小干扰RNA适当地包含约1-约50个核苷酸(nt)。在非限制性实施方案的实例中,siRNA可包含约5-约40 nt、约5-约30 nt、约10-约30 nt、约15-约25 nt、或约20-25个核苷酸。
适当寡核苷酸的挑选通过使用电脑程序来促进,该程序自动比对核酸序列并指出具有同一性或同源性的区。将这类程序用于比较通过例如搜索诸如GenBank等的数据库或通过测序PCR产物而获得的核酸序列。对来自一系列物种的核酸序列的比较,允许选择在物种之间显示适度同一性的核酸序列。在未测序基因的情况下,进行DNA印迹来确定在靶物种和其他物种的基因之间的同一性程度。如本领域众所周知的,通过在不同的严格程度下进行DNA印迹,可能获得同一性的近似衡量。这些程序允许选择以下寡核苷酸,其对待控制的受试者中的靶核酸序列表现出高度的互补性,并且对其他物种中的相应核酸序列表现出较低程度的互补性。本领域的技术人员将认识到,在挑选用于本发明的适当的基因区方面具有相当大的自由。
“酶促RNA”意为具有酶促活性的RNA分子(Cech, (1988) J. American. Med.Assoc. 260, 3030-3035)。酶促核酸(核酶)通过首先结合靶RNA来起作用。这类结合通过酶促核酸的靶结合部分进行,所述靶结合部分保持紧密靠近进行切割靶RNA的分子的酶促部分。因此,酶促核酸首先识别而后通过碱基配对结合靶RNA,且一旦结合到正确的位点,即进行酶促切割靶RNA。
“诱饵RNA”意为模拟配体的天然结合域的RNA分子。因此诱饵RNA与天然结合靶标竞争与特异性配体的结合。例如,已显示HIV反式激活应答(TAR) RNA的过表达可充当“诱饵”并有效地结合HIV tat蛋白,从而阻止其结合到在HIV RNA中编码的TAR序列(Sullenger等,(1990) Cell, 63, 601- 608)。这意指特定实例。本领域的技术人员将认识到,这只是一个实例,而其他的实施方案可使用本领域一般已知的技术容易地产生。
本文所用的术语“单体”通常指以下单体,其通过磷酸二酯键或其类似物连接以形成大小范围从少量单体单元(例如从约3-4)到约数百个单体单元的寡核苷酸。磷酸二酯键的类似物包括:硫代磷酸酯、二硫代磷酸酯、甲基膦酸酯、硒代磷酸酯、氨基磷酸酯等,如下文更充分地描述。
术语“核苷酸”涵盖天然存在的核苷酸和非天然存在的核苷酸。本领域的技术人员应清楚的是,先前认为“非天然存在”的多种核苷酸后来已在自然中发现。因此,“核苷酸”不仅包括已知的含嘌呤和嘧啶杂环的分子,而且还包括其杂环类似物和互变异构体。其他类型的核苷酸的说明性实例为以下分子,其含有腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、嘌呤、黄嘌呤、二氨基嘌呤、8-氧代-N6-甲基腺嘌呤、7-脱氮杂黄嘌呤、7-脱氮杂鸟嘌呤、N4,N4-桥亚乙基胞嘧啶(ethanocytosin)、N6,N6-桥亚乙基-2,6-二氨基嘌呤、5-甲基胞嘧啶、5-(C3-C6)-炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、假异胞嘧啶、2-羟基-5-甲基-4-三唑并吡啶、异胞嘧啶、异鸟嘌呤、肌苷和在Benner等美国专利第5,432,272号中描述的“非天然存在的”核苷酸。术语“核苷酸”意在涵盖这些实例以及其类似物和互变异构体中的每一个和全部。尤其令人关注的核苷酸为含腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶的核苷酸,其被认为是有关人中的治疗和诊断应用的天然存在核苷酸。核苷酸包括天然2’-脱氧和2’-羟基糖,例如,如Kornberg和Baker, DNA复制(DNA Replication), 第2版 (Freeman, SanFrancisco, 1992)中所述的以及其类似物。
提及核苷酸的“类似物”包括具有经修饰的碱基部分和/或经修饰的糖部分的合成核苷酸(参见例如,由Scheit,核苷酸类似物(Nucleotide Analogs),John Wiley, NewYork, 1980;Freier和Altmann, (1997) Nucl. Acid. Res., 25(22), 4429-4443,Toulmé, J.J., (2001) Nature Biotechnology 19:17-18;Manoharan M., (1999) Biochemicaet Biophysica Acta 1489:117-139;Freier S. M., (1997) Nucleic Acid Research,25:4429-4443, Uhlman, E., (2000) Drug Discovery & Development, 3: 203-213,Herdewin P., (2000) Antisense & Nucleic Acid Drug Dev., 10:297-310一般描述的);2’-O,3’-C-连接的[3.2.0]二环阿糖核苷(参加例如N.K Christiensen.等,(1998) J.Am. Chem. Soc., 120: 5458-5463;Prakash TP, Bhat B. (2007) Curr Top Med Chem.7(7):641-9;Cho EJ等, (2009) Annual Review of Analytical Chemistry, 2, 241-264)。这类类似物包括设计以增强结合特性的合成核苷酸,所述结合特性为例如双链体或三链体稳定性、特异性等。
本文所用的“杂交”意为寡聚化合物的基本上互补链的配对。一种配对的机理涉及寡聚化合物的链的互补核苷或核苷酸碱基(核苷酸)之间的氢键合,其可为沃森-克里克、Hoögsteen或反Hoögsteen氢键合。例如,腺嘌呤和胸腺嘧啶为互补的核苷酸,其通过形成氢键配对。杂交可在各种环境下发生。
反义化合物为“可特异地杂交的”,如果所述化合物与靶核酸的结合干扰靶核酸的正常功能而导致功能和/或活性的调节,并且在需要特异性结合的条件下存在足够程度的互补性来避免所述反义化合物与非靶核酸序列的非特异性结合,所述条件即在体内测定或治疗性处理情况中的生理条件下,以及其中在体外测定情况下进行测定的条件下。
本文所用的短语“严格杂交条件”或“严格条件”是指以下条件,在该条件下本发明的化合物与其靶序列杂交,但与最少数量的其他序列杂交。严格条件为序列依赖的且在不同环境下将不同,在本发明的文段中,在其下寡聚化合物与靶序列杂交的“严格条件”由寡聚化合物的性质和组成以及正在其中研究它们的试验来确定。一般而言,严格杂交条件包括低浓度(<0.15M)的含有诸如Na++或K++等无机阳离子的盐(即,低离子强度)、温度高于20℃-25℃、低于寡聚化合物:靶序列复合体的Tm,以及存在变性剂,例如甲酰胺、二甲基甲酰胺、二甲基亚砜,或去污剂十二烷基硫酸钠(SDS)。例如,杂交率对于每1%甲酰胺减少1.1%。高严格杂交条件的实例为0.1X氯化钠-柠檬酸钠缓冲液(SSC)/0.1% (w/v) SDS、60℃下达30分钟。
本文所用的“互补的”是指在一条或两条寡聚链上两个核苷酸之间精确配对的能力。例如,如果在反义化合物的某个位置上的核碱基能够与在靶核酸的某个位置上的核碱基氢键合,所述靶核酸为DNA、RNA或寡核苷酸分子,则认为所述寡核苷酸和所述靶核酸之间氢键合的位置为互补位置。当可彼此氢键合的核苷酸占据了每个分子中足够数量的互补位置时,寡聚化合物和另外的DNA、RNA或寡核苷酸分子为彼此互补的。因此,“可特异性杂交的”和“互补的”为以下术语,其用于表示在足够数量的核苷酸上有足够程度的精确配对或互补性,使得稳定和特异的结合发生在寡聚化合物和靶核酸之间。
据本领域了解,寡聚化合物的序列不需要与其可特异地杂交的靶核酸的序列100%互补。此外,寡核苷酸可在一个或多个区段上杂交,使得间插或邻近的区段不涉及杂交事件(例如,环结构、错配或发夹结构)。本发明的寡聚化合物包含与其靶向的靶核酸序列内的靶区至少约70%、或至少约75%、或至少约80%、或至少约85%、或至少约90%、或至少约95%、或至少约99%的序列互补性。例如,其中反义化合物的20个核苷酸中有18个与靶区互补且因而会特异地杂交的反义化合物,表示90%互补性。在此实例中,余下的非互补核苷酸可与互补核苷酸是聚簇或散布的且不需要彼此邻接或邻接互补核苷酸。因此,长度为18个核苷酸的反义化合物具有4(四)个非互补核苷酸,该非互补核苷酸位于与靶核酸完全互补的两个区的侧翼,所述反义化合物会具有与靶核酸77.8%的总互补性,因此落入本发明的范围内。反义化合物与靶核酸区的互补性百分比可使用本领域已知的BLAST程序(基本局部比对搜索工具)和PowerBLAST程序常规地确定(Altschul等, (1990) J. Mol. Biol., 215, 403-410;Zhang和Madden, (1997) Genome Res., 7, 649-656)。同源性、序列同一性或互补性百分比可通过例如Gap程序(Wisconsin序列分析包,Unix操作系统版本8, Genetics ComputerGroup, University Research Park, Madison Wis.)使用默认设置来确定,该程序使用Smith和Waterman的算法(Adv. Appl. Math., (1981) 2, 482-489)。
本文所用的术语“解链温度(Tm)”是指以下温度,在限定的离子强度、pH和核酸浓度下,在该温度下平衡时50%与靶序列互补的寡核苷酸与靶序列杂交。典型地,对于短寡核苷酸(例如,10-50个核苷酸)而言严格条件为以下条件,其中盐浓度至少为约0.01-1.0 MNa离子浓度(或其他盐),pH 7.0-8.3且温度至少为约30℃。严格条件也可通过外加诸如甲酰胺等去稳定剂来达到。
本文所用的“调节”意为在基因表达方面的增加(刺激)或减少(抑制)。
术语“变体”,当用于多核苷酸序列的情况下时,可包括有关野生型基因的多核苷酸序列。此定义也可包括,例如,“等位基因的”、“剪接”、“物种”或“多态的”变体。剪接变体可具有与参比分子显著的同一性,但因为在mRNA加工期间外显子的可变剪接而通常具有更多或更少数量的多核苷酸。对应的多肽可具有附加的功能域或不存在域。物种变体为在不同物种之间不同的多核苷酸序列。本发明中尤其实用的是野生型基因产物的变体。变体可由核酸序列中的至少一个突变产生并可导致产生改变的mRNA或者其结构或功能可能改变或不变的多肽。任何给定的天然或重组基因可不具有、具有一个或许多等位基因形式。产生变体的常见突变变化一般归因于核苷酸的自然缺失、添加或取代。这些变化类型中的每一个可单独或与其他类型联合发生,在给定序列中发生一次或多次。
产生的多肽一般将具有相对于彼此的显著的氨基酸同一性。多态变体为在给定物种的个体之间特定基因的多核苷酸序列的变化。多态变体也可包括“单核苷酸多态性”(SNP)或单碱基突变,其中多核苷酸序列因一个碱基而不同。SNP的存在可指示例如具有疾病状态倾向(即与抗性相对的易感性)的某个种群。
衍生多核苷酸包括经过化学修饰的核酸,例如用烷基、酰基或氨基置换氢。衍生物(例如,衍生寡核苷酸)可包含非天然存在的部分,例如改变的糖部分或糖间键。这些中示例性的是硫代磷酸酯及本领域已知的其他含硫的种类。衍生核酸也可含有标记,包括放射性核苷酸、酶、荧光剂、化学发光剂、显色剂、底物、辅因子、抑制剂、磁性颗粒,等等。
“衍生的”多肽或肽为经修饰的多肽或肽,例如,通过糖基化、聚乙二醇化、磷酸化作用、硫酸盐化作用、还原/烷基化、酰化、化学偶联或温性福尔马林处理。也可将衍生物修饰以含有可检测标记(直接地或间接地),包括但不限于放射性同位素、荧光和酶标记。
本文所用的术语“动物”或“患者”意在包括例如人、棉羊、麋鹿、鹿、长耳鹿、貂、哺乳动物、猴、马、牛、猪、山羊、狗、猫、大鼠、小鼠、鸟、鸡、爬行动物、鱼、昆虫和蜘蛛类。
“哺乳动物”涵盖通常在医疗护理下的温血哺乳动物(例如,人和驯养动物)。实例包括猫科动物、犬、马、牛科动物和人,以及仅仅人。
“处理”或“治疗”涵盖对哺乳动物中疾病状态的治疗,并包括:(a)防止疾病状态出现于哺乳动物中,特别是当这类哺乳动物倾向于疾病状态但尚未诊断为患有该疾病状态时;(b)抑制疾病状态,例如,阻止其发展;和/或(c)减轻疾病状态,例如,引起疾病状态的退行直到达到所需的终末点。治疗也包括改善疾病的症状(例如,减少疼痛或不适),其中这类改善可直接或可非直接地影响疾病(例如,原因、传递、表达等)。
本文所用的“癌症”是指在哺乳动物中发现的所有类型的癌症或新生物或恶性肿瘤,包括但不限于:白血病、淋巴瘤、黑素瘤、癌和肉瘤。癌症自身表现为包含癌症恶性细胞的“肿瘤”或组织。肿瘤的实例包括肉瘤和癌,例如但不限于:纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤(Ewing's tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、维尔姆斯氏肿瘤(Wilms' tumor)、子宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、成神经细胞瘤和视网膜母细胞瘤。可通过依照本发明的公开组合物治疗的其它癌症,包括但不限于,例如,何杰金病、非何杰金淋巴瘤、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、横纹肌肉瘤、原发性血小板增多症、原发性巨球蛋白血症、小细胞肺肿瘤、原发性脑肿瘤、胃癌、结肠癌、恶性胰腺胰岛素瘤(insulanoma)、恶性类癌、膀胱癌、恶化前皮肤病损、睾丸癌、淋巴瘤、甲状腺癌、成神经细胞瘤、食管癌、生殖泌尿道癌、恶性高钙血症、子宫颈癌、子宫内膜癌、肾上腺皮质癌和前列腺癌。
“炎症”是指全身性炎性病况以及局部地与单核细胞、白细胞和/或中性粒细胞的迁移和吸引有关的病况。炎症的实例包括但不限于,因以下引发的炎症:感染致病生物(包括革兰氏阳性菌、革兰氏阴性菌、病毒、真菌、以及寄生物,例如原生动物和蠕虫)、移植排斥(包括实质器官的排斥,例如肾、肝、心、肺或角膜,以及骨髓移植的排斥,包括移植物抗宿主病(GVHD))或者局限性慢性或急性自身免疫反应或变态反应。自身免疫性疾病包括急性肾小球肾炎;类风湿性或反应性关节炎;慢性肾小球肾炎;炎性肠病,例如克罗恩氏病、溃疡性结肠炎和坏死性小肠结肠炎;与粒细胞输注有关的综合征;炎性皮肤病,例如接触性皮炎、特应性皮炎、银屑病;系统性红斑狼疮(SLE);自身免疫性甲状腺炎、多发性硬化、以及糖尿病的某些形式、或任何其它自体免疫状态(其中受试者自身免疫系统的攻击导致病理性组织破坏)。变态反应包括变应性哮喘、慢性支气管炎、急性和迟发型超敏反应。全身性炎性疾病状态包括与创伤、烧伤、缺血事件后的再灌注(例如在心、脑、肠或外周脉管系统中的血栓形成事件,包括心肌梗死和中风)、脓毒症、ARDS或多器官功能障碍综合征相关的炎症。炎性细胞募集也在粥样硬化斑块中发生。炎症包括但不限于,非何杰金淋巴瘤、韦格纳肉芽肿病、桥本甲状腺炎、肝细胞癌、胸腺萎缩、慢性胰腺炎、类风湿性关节炎、反应性淋巴样增生、骨关节炎、溃疡性结肠炎、乳头状癌、克罗恩氏病、溃疡性结肠炎、急性胆囊炎、慢性胆囊炎、肝硬化、慢性涎腺炎、腹膜炎、急性胰腺炎、慢性胰腺炎、慢性胃炎、子宫肌腺病、子宫内膜异位、急性子宫颈炎、慢性子宫颈炎、淋巴样增生、多发性硬化、继发于特发性血小板减少性紫癜的肥大、原发性IgA肾病、系统性红斑狼疮、银屑病、肺气肿、慢性肾盂肾炎、以及慢性膀胱炎。
心血管疾病或障碍包括可引起缺血或者由心脏的再灌注引发的那些病症。实例包括但不限于,动脉粥样硬化、冠状动脉疾病、肉芽肿性心肌炎、慢性心肌炎(非肉芽肿性)、原发性肥大性心肌病、外周动脉病(PAD)、中风、心绞痛、心肌梗死、由心搏停止引发的心血管组织损伤、由心脏转流引发的心血管组织损伤、心源性休克,以及相关的病况,所述病况会是本领域普通技术人员已知的,或涉及心脏或脉管系统的机能障碍或组织损伤,特别是但不限于,与TTP激活有关的组织损伤。CVS疾病包括但不限于,动脉粥样硬化、肉芽肿性心肌炎、心肌梗死、继发于瓣膜性心脏病的心肌纤维化、无梗死形成的心肌纤维化、原发性肥大性心肌病、以及慢性心肌炎(非肉芽肿性)。
多核苷酸和寡核苷酸组合物和分子
靶标:在一个实施方案中,靶标包括三重四脯氨酸(TTP)的核酸序列,包括但不限于与TTP有关的有义和/或反义非编码和/或编码序列。
三重四脯氨酸(TTP;也称为锌指蛋白36同源物)(Zfp-36)是一种RNA-结合蛋白质,其调节肿瘤坏死因子α (TNFa) mRNA的稳定性。TTP的表达和它的磷酸化受到p38途径的调节。TTP也是一种具有新型锌指结构的调节蛋白质,参与调节针对生长因子的应答,并已实验显示能够结合锌。
在优选的实施方案中,反义寡核苷酸用于预防或治疗与TTP家族成员相关的疾病或障碍。可用由使用反义化合物获得的干细胞再生的细胞/组织治疗的示例性三重四脯氨酸(TTP)介导的疾病或障碍包括:三重四脯氨酸缺陷综合症、心血管疾病或障碍、心脏损伤(例如选自如下的心脏损伤:血流动力学超载、心肌再灌注损伤、肥厚型心肌病、终末期充血性心力衰竭和缺血性病症或其类似心肌梗塞和不稳定型心绞痛等的后果)、关节炎、炎症、关节和皮肤炎症、AIDS、炎症性肠病、克罗恩病、溃疡性结肠炎、癌症、肥胖、代谢综合征、肥胖相关的代谢性并发症、自身免疫性疾病或障碍、恶病质、髓细胞增生、骨骼肌损伤。
在一个优选的实施方案中,寡核苷酸对于TTP的多核苷酸(其包括但不限于非编码区)而言为特异的。TTP靶标包括TTP的变体;TTP的突变体,包括SNP;TTP的非编码序列;等位基因、片段等。优选所述寡核苷酸为反义RNA分子。
依照本发明的实施方案,靶核酸分子不单独限于TTP多核苷酸,而是扩展到TTP的任何同种型、受体、同源物、非编码区等。
在另一个优选的实施方案中,寡核苷酸靶向TTP靶标的天然反义序列(针对编码和非编码区的天然反义物),所述TTP靶标包括但不限于其变体、等位基因、同源物、突变体、衍生物、片段和互补序列。优选所述寡核苷酸为反义RNA或DNA分子。
在另一个优选的实施方案中,本发明的寡聚化合物也包括变体,其中在所述化合物的一个或多个核苷酸位置上存在不同的碱基。例如,如果第一个核苷酸为腺嘌呤,则可产生在此位置含有胸苷、鸟苷、胞苷或其他天然或非天然核苷酸的变体。这可在所述反义化合物的任何位置上完成。然后使用本文所述的方法来检测这些化合物以确定其抑制靶核酸的表达的能力。
在一些实施方案中,反义化合物与靶标之间的同源性、序列同一性或互补性为约50%-约60%。在一些实施方案中,同源性、序列同一性或互补性为约60%-约70%。在一些实施方案中,同源性、序列同一性或互补性为约70%-约80%。在一些实施方案中,同源性、序列同一性或互补性为约80%-约90%。在一些实施方案中,同源性、序列同一性或互补性为约90%、约92%、约94%、约95%、约96%、约97%、约98%、约99%或约100%。
反义化合物在以下情况时为可特异性杂交的:所述化合物与靶核酸的结合干扰靶核酸的正常功能而引起活性损失,并且在需要特异性结合的条件下存在足够程度的互补性以避免所述反义化合物与非靶核酸序列的非特异性结合。这类条件包括,即,在体内测定或治疗性处理情况中的生理条件,以及其中在体外测定情况下进行测定的条件。
反义化合物,不论DNA、RNA、嵌合的、取代的等等,在以下情况时为可特异性杂交的:所述化合物与靶DNA或RNA分子的结合干扰靶DNA或RNA的正常功能而引起效用损失,并且在需要特异性结合的条件下存在足够程度的互补性以避免所述反义化合物与非靶序列的非特异性结合,所述条件即在体内测定或治疗性处理情况中的生理条件下,以及在体外测定情况下在其中进行测定的条件下。
在另一个优选的实施方案中,靶向TTP调节TTP的表达或功能,TTP包括但不限于使用例如PCR、杂交等鉴定和扩增的反义序列、一个或多个如SEQ ID NO: 3-5所述的序列,等等。在一个实施方案中,表达或功能与对照相比为增量调节的。在另一个优选的实施方案中,表达或功能与对照相比为减量调节的。
在另一个优选的实施方案中,寡核苷酸包括如SEQ ID NO: 6-10所述的核酸序列,包括使用例如PCR、杂交等鉴定和扩增的反义序列。这些寡核苷酸可包含一个或多个经修饰的核苷酸、较短或较长的片段、经修饰的键等。经修饰的键或核苷酸间键的实例包括硫代磷酸酯、二硫代磷酸酯等。在另一个优选的实施方案中,所述核苷酸包括磷衍生物。可连接到本发明的修饰寡核苷酸中的糖或糖类似物部分的磷衍生物(或经修饰的磷酸基),可为单磷酸酯、二磷酸酯、三磷酸酯、烷基磷酸酯、链烷磷酸酯、硫代磷酸酯等。上述磷酸酯类似物的制备,以及它们掺入到核苷酸、修饰核苷酸和寡核苷酸中本身也为已知的且无需在此描述。
反义物的特异性和灵敏性也被本领域的技术人员掌握用于治疗用途。已将反义寡核苷酸用作在动物和人的疾病状态治疗中的治疗部分。已将反义寡核苷酸安全和有效地施用给人,并且目前正在进行许多临床试验。因此已确定寡核苷酸可为有用的治疗形式,其可将经配置以在用于治疗细胞、组织和动物尤其人的治疗方案中有用。
在本发明的实施方案中,寡聚反义化合物(具体地寡核苷酸)结合到靶核酸分子并调节由靶基因编码的分子的表达和/或功能。待干扰的DNA功能包括例如复制和转录。待干扰的RNA功能包括所有的生活机能,例如RNA向蛋白质翻译位点的易位、蛋白质自RNA的翻译、产生一种或多种mRNA种类的RNA剪接,以及可由RNA参与或促进的催化活性。所述功能可被增量调节或受抑制,这取决于所需的功能。
反义化合物包括反义寡聚化合物、反义寡核苷酸、外部指导序列(EGS)寡核苷酸、可变剪接物、引物、探针和与靶核酸的至少一部分杂交的其他寡聚化合物。因此,这些化合物可以单链、双链、部分单链或环状寡聚化合物的形式引入。
在本发明的情况下,将反义化合物靶向到特定的核酸分子可为多步过程。所述过程通常以鉴定待调节其功能的靶核酸开始。此靶核酸可为,例如其表达与特定病症或疾病状态有关的细胞基因(或从基因转录的mRNA),或来自传染剂的核酸分子。在本发明中,所述靶核酸编码三重四脯氨酸(TTP)。
靶向过程通常也包括确定靶核酸内的至少一个靶区、区段或位点以用于发生反义相互作用,使得产生所需的效应,例如,表达的调节。在本发明的文段中,术语“区”定义为具有至少一个可识别结构、功能或特征的靶核酸的一部分。靶核酸区内为区段。“区段”定义为在靶核酸内区的较小或亚部分。本发明所用的“位点”定义为靶核酸内的位置。
在一个优选的实施方案中,反义寡核苷酸结合到三重四脯氨酸(TTP)的天然反义序列并调节三重四脯氨酸(TTP) (SEQ ID NO: 1)的表达和/或功能。反义序列的实例包括SEQ ID NO: 3-10。
在另一个优选的实施方案中,反义寡核苷酸结合到三重四脯氨酸(TTP)多核苷酸的一个或多个区段并调节三重四脯氨酸(TTP)的表达和/或功能。所述区段包含三重四脯氨酸(TTP)有义或反义多核苷酸的至少五个连续的核苷酸。
在另一个优选的实施方案中,反义寡核苷酸对三重四脯氨酸(TTP)的天然反义序列而言为特异的,其中所述寡核苷酸与三重四脯氨酸(TTP)的天然反义序列的结合调节三重四脯氨酸(TTP)的表达和/或功能。
在另一个优选的实施方案中,寡核苷酸化合物包括如SEQ ID NO: 6-10所述的序列、使用例如PCR、杂交等鉴定和扩增的反义序列。这些寡核苷酸可包含一个或多个修饰核苷酸、较短或较长的片段、经修饰的键等。经修饰的键或核苷酸间键的实例包括硫代磷酸酯、二硫代磷酸酯等。在另一个优选的实施方案中,所述核苷酸包括磷衍生物。可连接到本发明的修饰寡核苷酸中的糖或糖类似物部分的磷衍生物(或经修饰的磷酸基),可为单磷酸酯、二磷酸酯、三磷酸酯、烷基磷酸酯、链烷磷酸酯、硫代磷酸酯等。上述磷酸酯类似物的制备,以及它们掺入到核苷酸、修饰核苷酸和寡核苷酸中本身也为已知的且无需在此描述。
由于如本领域已知,翻译起始密码子通常为5'-AUG(在转录的mRNA分子中;在相应的DNA分子中为5'-ATG),因而翻译起始密码子也称为“AUG密码子”、“起始密码子”或“AUG起始密码子”。少数基因具有翻译起始密码子,其具有RNA序列5'-GUG、5'-UUG或5'-CUG;以及5'-AUA、5'-ACG和5'-CUG已显示在体内起作用。因此,术语“翻译起始密码子”和“起始密码子”可包括许多密码子序列,但在每个情况下起始氨基酸通常为甲硫氨酸(在真核生物中)或甲酰甲硫氨酸(在原核生物中)。真核和原核基因可具有两个或更多个备选起始密码子,其中的任何一个可优先地用于在特定细胞类型或组织中或在特定条件组下的翻译起始。在本发明的文段中,“起始密码子”和“翻译起始密码子”是指这样的一个或多个密码子,其在体内用于起始由编码三重四脯氨酸(TTP)的基因转录的mRNA的翻译,与这类密码子的一个或多个序列无关。基因的翻译终止密码子(或“终止密码子”)可具有三个序列中的一个,即,5'-UAA、5'-UAG和5'-UGA(对应的DNA序列分别为5'-TAA、5'-TAG和5'-TGA)。
术语“起始密码子区”和“翻译起始密码子区”是指从翻译起始密码子开始在任一方向上(即,5’或3’)包含约25-约50个连续的核苷酸的这类mRNA或基因的部分。类似地,术语“终止密码子区”和“翻译终止密码子区”是指从翻译终止密码子开始在任一方向上(即,5’或3’)包含约25-约50个连续的核苷酸的这类mRNA或基因的部分。因此,“起始密码子区”(或“翻译起始密码子区”)和“终止密码子区”(或“翻译终止密码子区”)均为可用本发明的反义化合物有效地靶向的区。
本领域已知的可读框(ORF)或“编码区”是指在翻译起始密码子和翻译终止密码子之间的区,也为可有效地靶向的区。在本发明的内容内,靶向的区为包含基因的可读框(ORF)的翻译起始或终止密码子的基因内区。
另一种靶区包括本领域已知的5’非翻译区(5’UTR),是指在翻译起始密码子的5’方向上的mRNA的部分,因此包括在mRNA的5’加帽位点和翻译起始密码子之间的核苷酸(或基因上对应的核苷酸)。再一种靶区包括本领域已知的3’非翻译区(3'UTR),是指在翻译终止密码子3’方向上的mRNA的部分,因此包括在mRNA的翻译终止密码子和3’末端之间的核苷酸(或基因上对应的核苷酸)。mRNA的5’加帽位点包含经由5’-5’三磷酸酯键连接到mRNA的5’最末端残基的N7-甲基化鸟苷残基。认为mRNA的5’帽区包括5’帽子结构本身以及邻近该加帽位点的前50个核苷酸。用于本发明的另一种靶区为5’帽区。
尽管一些真核mRNA转录物为直接翻译的,但是许多包含一个或多个称为“内含子”的区,其在翻译前被从转录物中切除。余下的(且因此翻译的)区称为“外显子”,并将其剪接在一起形成连续的mRNA序列。在一个实施方案中,靶向剪接位点(即,内含子-外显子连接处或外显子-内含子连接处)在疾病牵涉异常剪接或疾病牵涉特定剪接产物过度产生的状况中特别有用。因重排或缺失所致的异常融合连接处为靶位点的另一个实施方案。经由来自不同基因来源的两个(或更多个) mRNA的剪接过程产生的mRNA转录物称为“融合转录物”。内含子可使用靶向到例如DNA或前-mRNA的反义化合物来有效地靶向。
在另一个优选的实施方案中,反义寡核苷酸结合到靶多核苷酸的编码和/或非编码区并调节靶分子的表达和/或功能。
在另一个优选的实施方案中,反义寡核苷酸结合到天然反义多核苷酸并调节靶分子的表达和/或功能。
在另一个优选的实施方案中,反义寡核苷酸结合到有义多核苷酸并调节靶分子的表达和/或功能。
可变RNA转录物可产生自DNA的相同基因组区。这些可变转录物一般称为“变体”。更具体地,“前mRNA变体”为产生自相同的基因组DNA的转录物,其与产生自相同的基因组DNA的其他转录物在其起始或终止位置上不同且包含内含子和外显子序列二者。
当剪接期间切除了一个或多个外显子或内含子区、或其部分时,前mRNA变体产生更小的“mRNA变体”。因此,mRNA变体为经加工的前mRNA变体,并且由于剪接所致,每种独特的前mRNA变体必须总是产生独特的mRNA变体。这些mRNA变体也称为“可变剪接变体”。如果未发生前mRNA变体的剪接,则前mRNA变体与mRNA变体完全相同。
变体可通过使用可变信号启动或终止转录来产生。前mRNA和mRNA可具有多于一个起始密码子或终止密码子。起源于使用可变起始密码子的前mRNA或mRNA的变体称为该前mRNA或mRNA的“可变起始变体”。使用可变终止密码子的转录物称为该前mRNA或mRNA的“可变终止变体”。可变终止变体的一个具体类型为“聚腺苷酸变体”,其中所产生的多重转录物起因于转录机构对其中一种“聚腺苷酸终止信号”的可变选择,从而产生终止在独特的聚腺苷酸位点上的转录物。在本发明的文段内,本文所述的变体类型也为靶核酸的实施方案。
将反义化合物与之杂交的靶核酸上的位置定义为活性反义化合物靶向的靶区的至少5个核苷酸长的部分。
虽然将某些示例性靶区段的具体序列列举于此,但是本领域的技术人员会认识到,这些用于说明和描述在本发明范围内的具体实施方案。根据本公开内容,其他靶区段可由本领域普通技术人员容易地鉴定。
认为以下靶区段同样适合靶向,该靶区段长度为5-100个核苷酸并包含选自说明性的优选靶区段之内的至少五(5)个连续核苷酸段。
靶区段可包括DNA或RNA序列,其包含来自说明性优选靶区段之一的5’末端的至少5个连续核苷酸(余下的核苷酸为相同DNA或RNA的连续段,其开始于靶区段5’末端的紧接上游且持续到该DNA或RNA包含约5-约100个核苷酸为止)。类似优选的靶区段由以下DNA或RNA序列表示,该序列包含来自说明性优选靶区段之一的3’末端的至少5个连续核苷酸(余下的核苷酸为相同DNA或RNA的连续段,其开始于靶区段3’末端的紧接下游且持续到该DNA或RNA包含约5-约100个核苷酸为止)。本领域技术人员根据本文所说明的靶区段,无需过度试验就能够鉴定进一步优选的靶区段。
一旦鉴定一个或多个靶区、区段或位点,就选出与该靶足够互补的反义化合物,所述足够互补即充分良好且具有足够的特异性地杂交以得到所需的效果。
在本发明的实施方案中,寡核苷酸与特定靶标的反义链结合。所述寡核苷酸长度为至少5个核苷酸且可为合成的,使得每个寡核苷酸靶向重叠的序列,由此将寡核苷酸合成为覆盖靶多核苷酸的全长。靶标也包括编码区以及非编码区。
在一个实施方案中,优选通过反义寡核苷酸来靶向特定核酸。将反义化合物靶向到特定核酸为多步过程。该过程通常开始于鉴定其功能待调节的核酸序列。这可为,例如其表达与特定的病症或疾病状态有关的细胞基因(或从该基因转录的mRNA),或非编码多核苷酸,例如非编码RNA (ncRNA)。
可将RNA归类为(1)信使RNA (mRNA),其被翻译成蛋白,和(2)非编码蛋白的RNA(ncRNA)。ncRNA包括微小RNA、反义转录物和包含高密度的终止密码子并缺少任何广泛的“可读框”的其他转录单元(TU)。许多ncRNA似乎开始于蛋白编码基因座的3’非翻译区(3'UTR)中的起始位点。ncRNA常常为罕见的且至少一半已由FANTOM协会测序的ncRNA似乎未聚腺苷酸化。大多数研究者因为明显的原因而关注经加工并输出到细胞质的聚腺苷酸化mRNA。近来,已显示非聚腺苷酸化核RNA的群体可非常巨大,且许多这类转录物产生于所谓的基因内区(Cheng, J.等,(2005) Science 308 (5725), 1149-1154; Kapranov, P.等,(2005). Genome Res 15 (7), 987-997)。ncRNA调节基因表达的机制可为通过与靶转录物的碱基配对。通过碱基配对起作用的RNA可分组成(1)顺式编码RNA,其在相同的基因位置、但在其所作用的RNA相反的链上编码,因此显示对其靶标完美的互补性,和(2)反式编码RNA,其在与其所作用的RNA不同的染色体位置上编码,一般不表现出与其靶标完美的碱基配对潜能。
不希望受到理论的约束,通过本文所述的反义寡核苷酸来扰乱反义多核苷酸,可改变相应有义信使RNA的表达。然而,此调节可为不一致的(反义敲减导致信使RNA上升)或一致的(反义敲减导致伴随的信使RNA下降)。在这些情况下,可将反义寡核苷酸靶向到反义转录物的重叠或非重叠部分,引起其敲减或隔离。编码以及非编码反义物可以相同的方式来靶向,并且任一种类别均能够调节相应有义转录物——以一致或不一致的方式。用于鉴定针对靶标使用的新寡核苷酸的策略可基于通过反义寡核苷酸或任何其他调节所需靶标的方法来敲减反义RNA转录物。
策略1:在不一致调节的情况下,敲减所述反义转录物提升常规(有义)基因的表达。若后者基因编码已知或假定的药物靶标,则其反义配对物的敲减可预料到地模拟受体激动剂或酶刺激剂的作用。
策略2:在一致调节的情况下,可伴随地敲减反义和有义转录物两者,从而达到常规(有义)基因表达的协同下降。如果例如将反义寡核苷酸用于进行敲减,则此策略可用于应用针对有义转录物靶向的一种反义寡核苷酸和针对相应反义转录物的另一种反义寡核苷酸,或同时靶向重叠的有义和反义转录物的单个有力对称的反义寡核苷酸。
根据本发明,反义化合物包括反义寡核苷酸、核酶、外部指导序列(EGS)寡核苷酸、siRNA化合物、单链或双链RNA干扰(RNAi)化合物(例如siRNA化合物),以及与靶核酸的至少一部分杂交且调节其功能的其他寡聚化合物。因此,其可为DNA、RNA、DNA样、RNA样、或其混合物,或可为这些中的一种或多种的模拟物。这些化合物可为单链、双链、环状或发夹寡聚化合物且可包含结构元件,例如内部或末端突起、错配或环。将反义化合物常规地制备为线性的但可被连接,或者另外制备成环状和/或分枝的。反义化合物可包括构建体,例如杂交以形成完全或部分双链化合物的两条链,或具有足够自我互补性以允许杂交并形成完全或部分双链化合物的单链。可将所述两条链内部连接而留下自由的3’或5’末端,或可将其连接形成连续的发夹结构或环。发夹结构可在5’或3’末端上包含突出端,产生单链特征的延伸。所述双链化合物任选可在末端上包含突出端。进一步的修饰可包括与末端之一、经挑选的核苷酸位置、糖位置或与核苷酸间键之一连接的缀合基团。或者,所述两条链可经由非核酸部分或连接基团来连接。当仅由一条链形成时,dsRNA可呈自我互补的发夹型分子形式,其在其自身上对折形成双链体。因此,所述dsRNA可为完全或部分双链的。基因表达的特异性调节可通过在转基因细胞系中稳定表达dsRNA发夹来完成,然而,在一些实施方案中,基因表达或功能为增量调节的。当形成自两条链,或呈在其自身上对折形成双链体的自身互补发夹型分子形式的单链时,所述两条链(或单链的双链体形成区)为以沃森-克里克模式碱基配对的互补RNA链。
一旦引入系统,本发明的化合物可引起一种或多种酶或结构蛋白的作用以实现靶核酸的切割或其他修饰,或可经由基于占据的机制来运作。一般而言,核酸(包括寡核苷酸)可描述为“DNA样”(即,一般具有一个或多个2’脱氧糖和一般地T而不是U碱基)或“RNA样”(即,一般具有一个或多个2’羟基或2’修饰的糖和一般U而不是T碱基)。核酸螺旋可采取多于一种类型的结构,最普通地A和B型。据认为,一般而言,具有B型样结构的寡核苷酸为“DNA样”而具有A型样结构的寡核苷酸为“RNA样”。在一些(嵌合的)实施方案中,反义化合物可包含A和B型区两者。
在另一个优选的实施方案中,所需的寡核苷酸或反义化合物,包括以下中的至少一种:反义RNA、反义DNA、嵌合反义寡核苷酸、包含经修饰的键的反义寡核苷酸、干扰RNA(RNAi)、短干扰RNA (siRNA);微小干扰RNA (miRNA);小时序RNA (stRNA);或短发夹RNA(shRNA);小RNA诱导的基因激活(RNAa);小激活RNA (saRNA)、或其组合。
dsRNA也可激活基因表达,这是已被称为“小RNA诱导的基因激活”或RNAa的机制。靶向基因启动子的dsRNA诱导相关基因的有效转录激活。在人细胞中使用合成dsRNA (称为“小激活RNA”(saRNA))证实RNAa。目前未知RNAa在其他生物体中是否为保守的。
已发现小双链RNA (dsRNA)(例如小干扰RNA(siRNA)和微小RNA(miRNA))是称为RNA干扰(RNAi)的进化保守机制的触发物。RNAi总是经由重构染色质来导致基因沉默,从而抑制转录、降解互补mRNA或阻断蛋白翻译。然而,在下文实施例章节详述的例子中,显示寡核苷酸增加三重四脯氨酸(TTP)多核苷酸和其编码产物的表达和/或功能。dsRNA也可充当小激活RNA (saRNA)。不希望受理论约束,通过靶向基因启动子中的序列,saRNA在称为dsRNA诱导的转录激活(RNAa)的现象中诱导靶基因表达。
在另一个实施方案中,本文鉴定的“优选靶区段”可用于筛选调节三重四脯氨酸(TTP)多核苷酸表达的另外化合物。“调节剂”为以下化合物,其减少或增加编码三重四脯氨酸(TTP)的核酸分子的表达并包含与优选靶区段互补的至少5-核苷酸部分。筛选方法包括以下步骤:使编码三重四脯氨酸(TTP)有义或天然反义多核苷酸的核酸分子的优选靶区段与一种或多种候选调节剂接触,以及选择一种或多种减少或增加编码三重四脯氨酸(TTP)多核苷酸的核酸分子表达的候选调节剂(例如SEQ ID NO: 6-10)。一旦显示一种或多种候选调节剂能够调节(例如减少或增加)编码三重四脯氨酸(TTP)多核苷酸的核酸分子表达,则可将所述调节剂用于三重四脯氨酸(TTP)多核苷酸功能的进一步调查研究,或用作依照本发明的研究、诊断或治疗剂。
靶向天然反义序列优选地调节靶基因的功能。例如,TTP基因(例如检索号NM_003407,图2)。在一个优选的实施方案中,靶标为TTP基因的反义多核苷酸。在一个优选的实施方案中,反义寡核苷酸靶向三重四脯氨酸(TTP)多核苷酸(例如检索号NM_003407, 图2)的有义和/或天然反义序列、其变体、等位基因、同种型、同源物、突变体、衍生物、片段和互补序列。优选所述寡核苷酸为反义分子且所述靶标包括反义和/或有义TTP多核苷酸的编码和非编码区。
本发明的优选靶区段也可与本发明的其各自互补的反义化合物结合,以形成稳定的双链(双链体)寡核苷酸。
本领域中已显示这类双链寡核苷酸部分经由反义机制来调节靶表达和调节翻译以及RNA加工。此外,所述双链部分可经受化学修饰(Fire等,(1998) Nature, 391, 806-811;Timmons和Fire, (1998) Nature, 395, 854;Timmons等,(2001) Gene, 263, 103-112;Tabara等,(1998) Science, 282, 430-431;Montgomery等,(1998) Proc. Natl.Acad. Sci. USA, 95, 15502-15507;Tuschl等,(1999) Genes Dev., 13, 3191-3197;Elbashir等,(2001) Nature, 411, 494-498;Elbashir等,(2001) Genes Dev. 15, 188-200)。例如,已显示这类双链部分通过所述双链体的反义链与靶标的典型杂交来抑制该靶标,从而触发靶标的酶促降解(Tijsterman等,(2002) Science, 295, 694-697)。
在一个优选的实施方案中,反义寡核苷酸靶向三重四脯氨酸(TTP)多核苷酸(例如检索号NM_003407)、其变体、等位基因、同种型、同源物、突变体、衍生物、片段和互补序列。优选所述寡核苷酸为反义分子。
依照本发明的实施方案,靶核酸分子不单独限于三重四脯氨酸(TTP)而是延伸到三重四脯氨酸(TTP)分子的任何同种型、受体、同源物等等。
在另一个优选的实施方案中,寡核苷酸靶向TTP多核苷酸的天然反义序列(例如,如SEQ ID NO: 3-5所述的多核苷酸),以及其任何变体、等位基因、同源物、突变体、衍生物、片段和互补序列。反义寡核苷酸的实例如SEQ ID NO: 6-10所述。
在一个实施方案中,所述寡核苷酸与三重四脯氨酸(TTP)反义物的核酸序列互补或结合,并调节三重四脯氨酸(TTP)分子的表达和/或功能,所述核酸序列包括但不限于与三重四脯氨酸(TTP)多核苷酸有关的非编码有义和/或反义序列。
在另一个优选的实施方案中,所述寡核苷酸与如SEQ ID NO: 3-5所述的TTP天然反义物的核酸序列互补或结合,并调节TTP分子的表达和/或功能。
在一个优选的实施方案中,寡核苷酸包含SEQ ID NO: 6-10的至少5个连续核苷酸的序列且调节三重四脯氨酸(TTP)分子的表达和/或功能。
多核苷酸靶标包括TTP,包括其家族成员、TTP的变体;TTP的突变体,包括SNP;TTP的非编码序列;TTP的等位基因;物种变体、片段等等。优选所述寡核苷酸为反义分子。
在另一个优选的实施方案中,靶向三重四脯氨酸(TTP)多核苷酸的寡核苷酸包括:反义RNA、干扰RNA (RNAi)、短干扰RNA (siRNA);微小干扰RNA (miRNA);小时序RNA(stRNA);或短发夹RNA (shRNA);小RNA诱导的基因激活RNAa);或小激活RNA (saRNA)。
在另一个优选的实施方案中,三重四脯氨酸(TTP)多核苷酸(例如SEQ ID NO: 3-5)的靶向调节这些靶标的表达或功能。在一个实施方案中,表达或功能相比于对照为增量调节的。在另一个优选的实施方案中,表达或功能相比于对照为减量调节的。
在另一个优选的实施方案中,反义化合物包括如SEQ ID NO: 6-10所述的序列。这些寡核苷酸可包含一个或多个经修饰的核苷酸、更短或更长的片段、经修饰的键等等。
在另一个优选的实施方案中,SEQ ID NO: 6-10包含一个或多个LNA核苷酸。
表1显示可用于在本发明的方法中的示例性反义寡核苷酸。
序列号 | 反义序列名称 | 序列 |
SEQ ID NO:6 | CUR-0364 | rGrArCrUrUrCrUrGrUrCrUrCrUrCrCrArGrUrCrCrCrUrGrArCrCrG |
SEQ ID NO:7 | CUR-0366 | rGrUrArCrUrCrUrGrUrCrUrUrUrCrGrCrArUrCrCrArUrGrGrCrArC |
SEQ ID NO:8 | CUR-0368 | rArArUrCrUrUrGrArCrCrUrCrArGrGrCrUrUrCrUrCrArUrUrGrGrA |
SEQ ID NO:9 | CUR-0370 | rGrArUrCrCrGrArCrCrCrUrGrArUrGrArArUrArUrGrCrCrArGrCrA |
SEQ ID NO:10 | CUR-0372 | rArUrCrUrUrCrArArUrCrGrCrArUrCrUrCrUrGrUrUrUrCrUrGrArG |
所需靶核酸的调节可以本领域已知的数个方式来进行。例如,反义寡核苷酸、siRNA等。酶促核酸分子(例如,核酶)为能够催化一种或多种不同反应(包括以核苷酸碱基序列特异的方式反复切割其他单独的核酸分子的能力)的核酸分子。这类酶促核酸分子可用于,例如,靶向几乎任何RNA转录物(Zaug等,324, Nature 429 1986;Cech, 260 JAMA3030, 1988;和Jefferies等,17 Nucleic Acids Research 1371, 1989)。
由于反式切割酶促核酸分子的序列特异性,其有望作为用于人类疾病的治疗剂(Usman & McSwiggen, (1995) Ann. Rep. Med. Chem. 30, 285-294;Christoffersen和Marr, (1995) J. Med. Chem. 38, 2023-2037)。可将酶促核酸分子设计成在细胞RNA背景下切割特定的RNA靶标。这类切割事件致使mRNA无功能且终止从该RNA的蛋白表达。以这种方式,可选择性地抑制与疾病状态有关的蛋白合成。
一般而言,带有RNA切割活性的酶促核酸通过首先与靶RNA结合来起作用。这类结合通过酶促核酸的靶结合部分来进行,该酶促核酸的靶结合部分保持紧密靠近进行切割靶RNA的分子的酶促部分。因此,所述酶促核酸首先识别而后通过互补的碱基配对与靶RNA结合,且一旦与正确的位点结合,即进行酶促地切割靶RNA。这类靶RNA的策略性切割将破坏其指导合成编码蛋白的能力。在酶促核酸结合和切割其RNA靶标之后,其从该RNA中释放以寻找另一个靶标且可反复结合和切割新靶标。
已使用诸如体外选择(进化)策略(Orgel, (1979) Proc. R. Soc. London, B205, 435)等数种途径来进化能够催化各种反应的新核酸催化剂,所述反应为例如磷酸二酯键和酰胺键的切割和连接(Joyce, (1989) Gene, 82, 83-87;Beaudry等,(1992)Science 257, 635-641;Joyce, (1992) Scientific American 267, 90-97;Breaker等,(1994) TIBTECH 12, 268;Bartel等,(1993) Science 261:1411-1418;Szostak, (1993)TIBS 17, 89-93;Kumar等,(1995) FASEB J., 9, 1183;Breaker, (1996) Curr. Op.Biotech., 7, 442)。
催化活性最佳的核酶的开发会显著地有助于以调节基因表达为目的而采用RNA切割核酶的任何策略。例如锤头状核酶在存在Mg2+辅因子的饱和(10 mM)浓度下,以约1 min-1的催化速率(kcat)起作用。已显示人造“RNA连接酶”核酶以约100 min-1的速率催化相应的自我修饰反应。此外,据了解具有由DNA组成的底物结合臂的某些经修饰的锤头状核酶,以接近100 min-1的倍数转换速率(multiple turn-over rate)催化RNA切割。最终,用某些核苷酸类似物置换在锤头的催化核心内的特定残基产生显示出在催化速率上多达10倍改进的修饰核酶。这些研究结果证实核酶可以以显著高于大多数天然自我切割核酶展示于体外的催化速率,促进化学转化。那么可能的是,可优化某些自我切割核酶的结构以产生最高的催化活性,或者可制备展示出显著更快的RNA磷酸二酯切割速率的全新RNA基序。
通过符合“锤头”模型的RNA催化剂来分子间切割RNA底物首先显示于1987年(Uhlenbeck, O. C. (1987) Nature, 328: 596-600)。将所述RNA催化剂回收且与多种RNA分子反应,证实其为真正催化性的。
基于“锤头”基序设计的催化性RNA已通过在催化性RNA中作出适当的碱基改变以维持与靶序列的必要碱基配对,来用于切割特定靶序列(Haseloff和Gerlach, (1988)Nature, 334, 585;Walbot和Bruening, (1988) Nature, 334, 196;Uhlenbeck, O. C.(1987) Nature, 328: 596-600;Koizumi, M.等,(1988) FEBS Lett., 228: 228-230)。这允许使用催化性RNA来切割特定靶序列,并指出根据“锤头”模型设计的催化性RNA可能在体内切割特定底物RNA(参见Haseloff和Gerlach, (1988) Nature, 334, 585;Walbot和Bruening, (1988) Nature, 334, 196;Uhlenbeck, O. C. (1987) Nature, 328: 596-600)。
RNA干扰(RNAi)已成为调节哺乳动物和哺乳动物细胞中基因表达的强大工具。此方法要求使用表达质粒或病毒以及加工成siRNA的小发夹RNA的编码序列,将小干扰RNA(siRNA)作为RNA本身或作为DNA递送。此系统能够有效将前siRNA转运到它们在其中活跃的细胞质中,并允许使用经调节的和组织特异的启动子用于基因表达。
在一个优选的实施方案中,寡核苷酸或反义化合物包括核糖核酸(RNA)和/或脱氧核糖核酸(DNA)的寡聚体或多聚体、或其模拟物、嵌合体、类似物或同源物。此术语包括由天然存在核苷酸、糖和共价核苷间(骨架)键组成的寡核苷酸以及类似地起作用的具有非天然存在部分的寡核苷酸。由于所需性质,例如,增强的细胞摄取、对靶核酸增强的亲和力以及在核酸酶存在时增大的稳定性,常常需要这类经修饰或取代的寡核苷酸超过天然形式。
根据本发明,寡核苷酸或“反义化合物”包括反义寡核苷酸(例如RNA、DNA、其模拟物、嵌合体、类似物或同源物)、核酶、外部指导序列(EGS)寡核苷酸、siRNA化合物、单链或双链RNA干扰(RNAi)化合物例如siRNA化合物、saRNA、aRNA,以及与靶核酸的至少一部分杂交且调节其功能的其他寡聚化合物。因此,它们可为DNA、RNA、DNA样、RNA样、或其混合物,或可为这些中的一种或多种的模拟物。这些化合物可为单链、双链、环状或发夹寡聚化合物且可包含结构元件,例如内部或末端突起、错配或环。将反义化合物常规地制备成线性但可经连接或者另外地制备成环状和/或分枝的。反义化合物可包括构建体,例如杂交以形成完全或部分双链化合物的两条链,或带有足够自我互补性以允许杂交并形成完全或部分双链化合物的单链。可将所述两条链内部连接而留下游离的3’或5’末端或可将其连接形成连续的发夹结构或环。发夹结构可在5’或3’末端上包含突出端,产生单链特征的延伸。双链化合物任选可在末端上包含突出端。进一步的修饰可包括与末端之一、经挑选的核苷酸位置、糖位置或核苷间键之一连接的缀合基团。备选地,所述两条链可经由非核酸部分或连接基团来连接。当形成自仅一条链时,dsRNA可采取自我互补的发夹型分子形式,其在其自身上对折形成双链体。因此,所述dsRNA可为完全或部分双链的。基因表达的特异性调节可通过dsRNA发夹在转基因细胞系中的稳定表达来完成(Hammond等,(1991) Nat. Rev. Genet., 2, 110-119;Matzke等,(2001) Curr. Opin. Genet. Dev., 11, 221-227;Sharp, (2001) GenesDev., 15, 485-490)。当形成自两条链或采取在其自身上对折形成双链体的自身互补的发夹型分子形式的单链时,所述两条链(或单链的双链体形成区)为以沃森-克里克模式碱基配对的互补RNA链。
一旦引入系统,本发明的化合物可引起一种或多种酶或结构蛋白的作用以实现靶核酸的切割或其他修饰,或可经由基于占据的机制来运作。一般而言,核酸(包括寡核苷酸)可描述为“DNA样”(即,一般具有一个或多个2’脱氧糖和,一般地,T而不是U碱基)或“RNA样”(即,一般具有一个或多个2’羟基或2’修饰的糖和,一般U而不是T碱基)。核酸螺旋可采取多于一种类型的结构,最普通地A和B型。据认为,一般而言,具有B型样结构的寡核苷酸为“DNA样”而具有A型样结构的寡核苷酸为“RNA样”。在一些(嵌合的)实施方案中,反义化合物可包含A和B型区两者。
依照本发明的反义化合物可包含约5-约80个核苷酸(即约5-约80个连接核苷)长度的反义部分。这是指反义化合物的反义链或部分的长度。换言之,本发明的单链反义化合物包含5-约80个核苷酸,而本发明的双链反义化合物(例如,dsRNA)包含5-约80个核苷酸长度的有义和反义链或部分。本领域普通技术人员将认识到,这包括5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79或80个核苷酸长度、或其之内任何范围的反义部分。
在一个实施方案中,本发明的反义化合物具有10-50个核苷酸长度的反义部分。本领域普通技术人员将认识到,这包括具有10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50个核苷酸长度、或其之内任何范围的反义部分的寡核苷酸。在一些实施方案中,寡核苷酸长度为15个核苷酸。
在一个实施方案中,本发明的反义或寡核苷酸化合物具有12或13-30个核苷酸长度的反义部分。本领域普通技术人员将认识到,这包括具有12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个核苷酸长度、或其之内任何范围的反义部分的反义化合物。
在另一个优选的实施方案中,本发明的寡聚化合物也包括其中不同的碱基存在于化合物中的一个或多个核苷酸位置上的变体。例如,如果第一个核苷酸为腺苷,那么可产生在此位置包含胸苷、鸟苷或胞苷的变体。这可在反义或dsRNA化合物的任何位置上进行。然后使用本文所述的方法来检测这些化合物以确定其抑制靶核酸表达的能力。
在一些实施方案中,反义化合物与靶标之间的同源性、序列同一性或互补性为约40%-约60%。在一些实施方案中,同源性、序列同一性或互补性为约60%-约70%。在一些实施方案中,同源性、序列同一性或互补性为约70%-约80%。在一些实施方案中,同源性、序列同一性或互补性为约80%-约90%。在一些实施方案中,同源性、序列同一性或互补性为约90%、约92%、约94%、约95%、约96%、约97%、约98%、约99%或约100%。
在另一个优选的实施方案中,反义寡核苷酸(例如,SEQ ID NO: 3-10中所述的核酸分子)包含一个或多个取代或修饰。在一个实施方案中,将核苷酸用锁定核酸(LNA)取代。
在另一个优选的实施方案中,寡核苷酸靶向与TTP有关的编码和/或非编码序列以及如SEQ ID NO: 1、3、4和5所述的序列有义和/或反义的核酸分子的一个或多个区。也将寡核苷酸靶向到SEQ ID NO: 1、3、4和5的重叠区。
本发明的某些优选的寡核苷酸为嵌合寡核苷酸。“嵌合寡核苷酸”或“嵌合体”,在本发明的背景中,为包含两个或更多个化学上不同区的寡核苷酸,每个区由至少一个核苷酸组成。这些寡核苷酸典型地包含赋予一种或多种有益特性(例如,对核酸酶的抗性增强、摄入细胞增强、对靶标增强的结合亲和力)的修饰核苷酸的至少一个区,以及作为能够切割RNA:DNA或RNA:RNA杂合体的酶底物的区。作为实例,核糖核酸酶H为细胞核酸内切酶,其切割RNA:DNA双链体的RNA链。核糖核酸酶H的活化因此导致RNA靶标的切割,从而大大地增强基因表达的反义调节效率。因此,当使用嵌合寡核苷酸时,与杂交到相同靶区的硫代磷酸酯脱氧寡核苷酸相比,常常可用较短的寡核苷酸获得相当的结果。RNA靶标的切割可通过凝胶电泳和必要时本领域已知的相关核酸杂交技术,常规地检测。在一个优选的实施方案中,嵌合寡核苷酸包含修饰成增加靶结合亲和力的至少一个区,并且通常包含充当核糖核酸酶H的底物的区。寡核苷酸对其靶标(在此情况下,编码ras的核酸)的亲和力通过测定寡核苷酸/靶标对的Tm来常规地确定,Tm为寡核苷酸与靶标解离的温度;解离以分光光度法检测。Tm越高,寡核苷酸对靶标的亲和力越大。
本发明的嵌合反义化合物可作为如上所述的两个或更多个寡核苷酸、修饰寡核苷酸、寡聚核苷和/或寡核苷酸模拟物的复合结构而形成。本领域亦已将这类化合物称为杂合体或gapmer。教导制备这类杂合结构的代表性美国专利包括但不限于,美国专利第5,013,830、5,149,797、5, 220,007、5,256,775、5,366,878、5,403,711、5,491,133、5,565,350、5,623,065、5,652,355、5,652,356和5,700,922号,每个通过引用结合于本文中。
在另一个优选的实施方案中,经修饰的寡核苷酸区包含在糖的2’位置上修饰的至少一个核苷酸,最优选2’-O烷基、2’-O-烷基-O-烷基或2’-氟修饰的核苷酸。在其它优选的实施方案中,RNA修饰包括在RNA 3’末端的嘧啶、脱碱基残基或反向碱基的核糖上的2’-氟、2’-氨基和2’O-甲基修饰。将这类修饰常规地掺入到寡核苷酸中,已显示这些寡核苷酸具有比2’-脱氧寡核苷酸对给定靶标更高的Tm (即,更高的靶结合亲和力)。这种增加的亲和力的作用为大大地增强基因表达的RNAi寡核苷酸抑制。核糖核酸酶H为切割RNA:DNA双链体的RNA链的细胞核酸内切酶;此酶的活化因此导致RNA靶标的切割,且因此可大大地增强RNAi抑制效率。RNA靶标的切割可通过凝胶电泳来常规地证实。在另一个优选的实施方案中,也修饰嵌合寡核苷酸以增强核酸酶抗性。细胞包含可降解核酸的各种核酸外切酶和核酸内切酶。已显示许多核苷酸和核苷修饰使掺入有它们的寡核苷酸比天然寡脱氧核苷酸对核酸酶消化更有抗性。核酸酶抗性通过将寡核苷酸与细胞提取物或分离的核酸酶溶液一起孵育并测定随时间推移剩余的完好寡核苷酸的程度(通常地通过凝胶电泳)来常规地测定。已修饰成增强其核酸酶抗性的寡核苷酸比未修饰寡核苷酸保持完好持续更长时间。已证实多种寡核苷酸修饰增强或赋予核酸酶抗性。包含至少一个硫代磷酸酯修饰的寡核苷酸为目前更优选的。在一些情况下,增强靶结合亲和力的寡核苷酸修饰也能够独立地增强核酸酶抗性。一些所需的修饰可在De Mesmaeker等,(1995) Acc. Chem. Res., 28:366-374中找到。
预想用于本发明的一些优选寡核苷酸的具体实例包括包含经修饰的骨架的那些,所述经修饰的骨架为例如硫代磷酸酯、磷酸三酯、甲基膦酸酯、短链烷基或环烷基糖间键或者短链杂原子或杂环的糖间键。最优选的为带有硫代磷酸酯骨架和带有杂原子骨架的寡核苷酸,特别地CH2 --NH--O--CH2、CH,--N(CH3)--O--CH2[称为亚甲基(甲亚氨基)或MMI骨架]、CH2 --O--N (CH3)--CH2、CH2 –N (CH3)--N (CH3)--CH2和O--N (CH3)--CH2 --CH2骨架,其中天然磷酸二酯骨架表示为O--P--O—CH。由De Mesmaeker等,(1995) Acc. Chem.Res. 28:366-374公开的酰胺骨架也为优选的。同样优选的为具有吗啉代骨架结构的寡核苷酸(Summerton和Weller,美国专利第5,034,506号)。在其他优选的实施方案中,将寡核苷酸的例如肽核酸(PNA)骨架、磷酸二酯骨架替换为聚酰胺骨架,核苷酸直接或间接地与聚酰胺骨架的氮杂氮原子结合(Nielsen等,(1991) Science 254, 1497)。寡核苷酸也可包含一个或多个取代的糖部分。优选的寡核苷酸在2’位置上包含下列中的一种:OH、SH、SCH3、F、OCN、OCH3 OCH3、OCH3 O(CH2)n CH3、O(CH2)n NH2或O(CH2)n CH3,其中n为1-约10;C1-C10低级烷基、烷氧基烷氧基、取代的低级烷基、烷芳基或芳烷基;Cl;Br;CN;CF3;OCF3;O--、S--、或N-烷基;O--、S--、或N-烯基;SOCH3;SO2 CH3;ONO2;NO2;N3;NH2;杂环烷基;杂环烷芳基;氨基烷基氨基;聚烷基氨基;取代的甲硅烷基;RNA切割基团;报道基团;嵌入剂;改进寡核苷酸药代动力学特性的基团;或改进寡核苷酸药效学特性的基团以及具有类似特性的其他取代基。优选的修饰包括2’-甲氧乙氧基[2'-O-CH2 CH2 OCH3,也称为2'-O-(2-甲氧乙基)] (Martin等,(1995) Helv. Chim. Acta, 78, 486)。其他优选的修饰包括2’-甲氧基(2'-O--CH3)、2’-丙氧基(2'-OCH2 CH2CH3)和2’-氟(2'-F)。类似的修饰也可在寡核苷酸的其他位置上进行,具体地在3’末端核苷酸上糖的3’位置和5’末端核苷酸的5’位置。寡核苷酸也可具有糖模拟物例如取代戊呋喃糖基基团的环丁基。
寡核苷酸也可另外或备选地包含核碱基(本领域常常简称为“碱基”)修饰或取代。本文所用的“未修饰的”或“天然的”核苷酸包括腺嘌呤(A)、鸟嘌呤(G)、胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰核苷酸包括在天然核酸中仅稀少或短暂地存在的核苷酸,例如,次黄嘌呤、6-甲基腺嘌呤、5-Me嘧啶、特别地5-甲基胞嘧啶(也称为5-甲基-2’脱氧胞嘧啶且常常在本领域中称为5-Me-C)、5-羟甲基胞嘧啶(HMC)、糖基HMC和龙胆二糖基HMC,以及合成核苷酸,例如,2-氨基腺嘌呤、2-(甲氨基)腺嘌呤、2-(咪唑基烷基)腺嘌呤、2-(氨烷基氨基)腺嘌呤或其他杂取代的烷基腺嘌呤、2-硫尿嘧啶、2-硫胸腺嘧啶、5-溴尿嘧啶、5-羟基甲基尿嘧啶、8-氮杂鸟嘌呤、7-脱氮杂鸟嘌呤、N6(6-氨己基)腺嘌呤和2,6-二氨基嘌呤(Kornberg,A., DNA Replication, W. H. Freeman & Co., San Francisco, 1980, 第75-77页;Gebeyehu, G., (1987)等,Nucl. Acids Res. 15:4513)。可包括本领域已知的“通用的”碱基,例如,肌苷。已显示5-Me-C取代增强核酸双链体的稳定性达0.6-1.2℃ (Sanghvi, Y.S.,载于Crooke, S. T.和Lebleu, B.,编辑, Antisense Research and Applications,CRC Press, Boca Raton, 1993, 276-278页)且为目前优选的碱基取代。
本发明的寡核苷酸的另一种修饰涉及以化学方法使一种或多种增强寡核苷酸的活性或细胞摄取的部分或缀合物与寡核苷酸连接。这类部分包括但不限于脂质部分,例如胆固醇部分、胆甾醇基部分(Letsinger等,(1989) Proc. Natl. Acad. Sci. USA 86,6553)、胆酸(Manoharan等,(1994) Bioorg. Med. Chem. Let. 4, 1053)、硫醚例如己基-S-三苯甲基硫醇(Manoharan等,(1992) Ann. N.Y. Acad. Sci. 660, 306;Manoharan等,(1993) Bioorg. Med. Chem. Let. 3, 2765)、巯基胆固醇(Oberhauser等,(1992) Nucl.Acids Res. 20, 533)、脂族链例如十二烷二醇或十一烷基残基(Saison-Behmoaras等,EMBO J. 1991, 10, 111;Kabanov等,(1990) FEBS Lett. 259, 327;Svinarchuk等,(1993) Biochimie 75, 49)、磷脂例如二-十六烷基-消旋-甘油或1,2-二-O-十六烷基-消旋-甘油-3-H-膦酸三乙铵(Manoharan等,(1995) Tetrahedron Lett. 36, 3651;Shea等,(1990) Nucl. Acids Res. 18, 3777)、聚胺或聚乙二醇链(Manoharan等,(1995)Nucleosides & Nucleotides, 14, 969)、或TTP触角(TTPantane)乙酸(Manoharan等,(1995) Tetrahedron Lett. 36, 3651)。包含亲脂性部分的寡核苷酸以及用于制备这类寡核苷酸的方法为本领域已知的,例如美国专利第5,138,045、5,218,105和5,459,255号。
无需将给定寡核苷酸中的所有位置一致地修饰,且实际上多于一种上述修饰可掺入到单个寡核苷酸中或甚至在寡核苷酸内的单个核苷内部。本发明也包括作为如上文中定义的嵌合寡核苷酸的寡核苷酸。
在另一个实施方案中,本发明的核酸分子与另一个部分缀合,所述部分包括但不限于脱碱基核苷酸、聚醚、聚胺、聚酰胺、肽、碳水化合物、脂质或聚碳氢化合物。本领域技术人员将认识到,可将这些分子在糖、碱基或磷酸基的数个位置上连接到一个或多个构成核酸分子的任何核苷酸。
依照本发明使用的寡核苷酸可通过众所周知的固相合成技术来便利和常规地制备。用于这类合成的设备由包括Applied Biosystems在内的数个供应商销售。也可使用用于这类合成的任何其他方法;寡核苷酸的实际合成完全在本领域普通技术人员的才能之内。亦众所周知的是使用类似技术来制备其他寡核苷酸,例如硫代磷酸酯和烷基化衍生物。还众所周知的是使用类似技术和市购经修饰的amidites和可控孔度玻璃(CPG)产品,例如生物素、荧光黄、吖啶、或补骨脂素修饰的amidites和/或CPG(可从Glen Research,Sterling VA购买),以合成荧光标记的、生物素化的或其他修饰的寡核苷酸,例如胆固醇修饰的寡核苷酸。
依照本发明,使用修饰(例如使用LNA单体)以增加寡核苷酸的效价、特异性和作用持续时间并拓宽其施用途径,所述寡核苷酸由诸如MOE、ANA、FANA、PS等当前的化学物质组成(Uhlman等,(2000) Current Opinions in Drug Discovery & Development第3卷第2期)。这可通过用LNA单体取代当前寡核苷酸中的一些单体来完成。LNA修饰的寡核苷酸可具有类似于母体化合物的大小或可更大或优选更小。优选这类LNA修饰寡核苷酸包含少于约70%、更优选少于约60%、最优选少于约50%的 LNA单体且其大小在约5-25个核苷酸之间,更优选在约12-20个核苷酸之间。
优选的修饰寡核苷酸骨架包括但不限于硫代磷酸酯、手性硫代磷酸酯、二硫代磷酸酯、磷酸三酯、氨烷基磷酸三酯、甲基和其他烷基膦酸酯包括3’烯基膦酸酯和手性膦酸酯、次磷酸酯、氨基磷酸酯包括3’-氨基氨基磷酸酯和氨烷基氨基磷酸酯、硫羰基氨基磷酸酯、硫羰基烷基膦酸酯、硫羰基烷基磷酸三酯,以及具有正常3’-5’键合的硼烷磷酸酯(boranophosphates)、这些的2’-5’连接类似物,以及具有反极性的那些,其中核苷单元的相邻对为3’-5’与5’-3’或2’-5’与5’-2’连接。也包括各种盐、混合盐和游离酸形式。
教导制备上述含磷键的代表性的美国专利包括但不限于,美国专利第3,687,808、4,469,863、4,476,301、5,023,243、5, 177,196、5,188,897、5,264,423、5,276,019、5,278,302、5,286,717、5,321,131、5,399,676、5,405,939、5,453,496、5,455, 233、5,466,677、5,476,925、5,519,126、5,536,821、5,541,306、5,550,111、5,563, 253、5,571,799、5,587,361和5,625,050号,每个通过引用结合于本文中。
优选的修饰寡核苷酸骨架(其中不包含磷原子),具有由短链烷基或环烷基核苷间键、混合杂原子和烷基或环烷基核苷间键、或一种或多种短链杂原子或杂环核苷间键形成的骨架。这些包括具有吗啉代键的骨架(部分由核苷的糖部分形成);硅氧烷骨架;硫化物、亚砜和砜骨架;甲乙酰基(formacetyl)和硫代甲乙酰基(thioformacetyl)骨架;亚甲基甲乙酰基和硫代甲乙酰基骨架;含烯骨架;氨基磺酸酯骨架;亚甲基亚氨基和亚甲基肼基骨架;磺酸酯或氨磺酰骨架;酰胺骨架;以及具有混合N、O、S和CH2组分部分的其他骨架。
教导制备上述寡聚核苷的代表性的美国专利包括但不限于,美国专利第5,034,506、5,166,315、5,185,444、5,214,134、5,216,141、5,235,033、5,264,562、5,264,564、5,405,938、5,434,257、5,466,677、5,470,967、5,489,677、5,541,307、5,561,225、5,596,086、5,602,240、5,610,289、5,602,240、5,608,046、5,610,289、5,618,704、5,623,070、5,663,312、5,633,360、5,677,437和5,677,439号,每个通过引用结合于本文中。
在其他优选的寡核苷酸模拟物中,将核苷酸单元的糖和核苷间键(即骨架),均用新基团置换。维持碱基单元用于与适当的核酸靶化合物杂交。一种这类寡聚化合物(已显示具有优秀的杂交特性的寡核苷酸模拟物),称为肽核酸(PNA)。在PNA化合物中,寡核苷酸的糖骨架替换为含酰胺的骨架,具体地氨乙基氨基乙酸骨架。将所述核碱基保留并直接或间接地与骨架的酰胺部分的氮杂氮原子结合。教导制备PNA化合物的代表性的美国专利包括但不限于,美国专利第5,539,082、5,714,331和5,719,262号,每个通过引用结合于本文中。PNA化合物的进一步教导可在Nielsen等,(1991)Science 254, 1497-1500中找到。
在本发明的另一个优选的实施方案中,带有硫代磷酸酯骨架的寡核苷酸和带有杂原子骨架的寡聚核苷,具体地- CH2-NH-O-CH2-,-CH2-N (CH3)-O-CH2-(称为亚甲基(甲亚氨基)或MMI骨架),- CH2-O-N (CH3)-CH2-、-CH2N(CH3)-N(CH3) CH2-和-O-N(CH3)-CH2-CH2-,其中天然磷酸二酯骨架表示为上文引用的美国专利第5,489,677号的-O-P-O-CH2-,以及上文引用的美国专利第5,602,240号的酰胺骨架。同样优选的为具有上文引用的美国专利第5,034,506号的吗啉代骨架结构的寡核苷酸。
修饰寡核苷酸也可包含一个或多个经取代的糖部分。优选的寡核苷酸在2’位置上包含下列中的一种:OH;F;O-、S-、或N-烷基;O-、S-、或N-烯基;O-、S-或N-炔基;或O烷基-O-烷基,其中所述烷基、烯基和炔基可为取代或未取代的C到CO烷基或C2到CO烯基和炔基。特别优选的为O (CH2)n OmCH3、O(CH2)n、OCH3、O(CH2)nNH2、O(CH2)nCH3、O(CH2)nONH2和O(CH2nON(CH2)nCH3)2,其中n和m可为1-约10。其他优选的寡核苷酸在2’位置上包含下列中的一种:C到CO、低级烷基、取代的低级烷基、烷芳基、芳烷基、O-烷芳基或O-芳烷基、SH、SCH3、OCN、Cl、Br、CN、CF3、OCF3、SOCH3、SO2CH3、ONO2、NO2、N3、NH2、杂环烷基、杂环烷芳基、氨烷基氨基、聚烷基氨基、取代的甲硅烷基、RNA切割基团、报道基团、嵌入剂、用于改进寡核苷酸药代动力学特性的基团、或用于改进寡核苷酸药效学特性的基团,以及具有类似特性的其他取代基。优选的修饰包括2’-甲氧乙氧基(2'-O-CH2CH2OCH3,也称为2’ -O-(2-甲氧乙基)或2'-MOE) (Martin等,(1995) Helv. Chim. Acta, 78, 486-504),即,烷氧基烷氧基基团。进一步优选的修饰包括2’-二甲基氨基氧基乙氧基,即O(CH2)2ON(CH3)2基团,也称为2'-DMAOE(如下文实施例中所述),以及2’-二甲基氨基乙氧基乙氧基(本领域也称为2’-O-二甲基氨基乙氧基乙基或2'- DMAEOE),即2'-O-CH2-O-CH2-N (CH2)2。
其他优选的修饰包括2’-甲氧基(2'-O CH3)、2’-氨基丙氧基(2'-OCH2CH2CH2NH2)和2’-氟(2'-F)。类似的修饰也可在寡核苷酸的其他位置上进行,具体地在3’末端核苷酸上或2’-5’连接的寡核苷酸中糖的3’位置以及5’末端核苷酸的5’位置。寡核苷酸也可具有糖模拟物例如取代戊呋喃糖基糖的环丁基部分。教导制备这类经修饰的糖结构的代表性的美国专利包括但不限于,美国专利第4,981,957、5,118,800、5,319,080、5,359,044、5,393,878、5,446,137、5,466,786、5,514,785、5,519,134、5,567,811、5,576,427、5,591,722、5,597,909、5,610,300、5,627,053、5,639,873、5,646, 265、5,658,873、5,670,633和5,700,920号,每个通过引用结合于本文中。
寡核苷酸也可包含核碱基(本领域常常简称为“碱基”)修饰或取代。本文所用的“未修饰的”或“天然的”核苷酸包括嘌呤碱基腺嘌呤(A)和鸟嘌呤(G),以及嘧啶碱基胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰核苷酸包括其他合成和天然核苷酸,例如5-甲基胞嘧啶(5-me-C)、5-羟甲基胞嘧啶、黄嘌呤、次黄嘌呤、2-氨基腺嘌呤、腺嘌呤和鸟嘌呤的6-甲基和其他烷基衍生物、腺嘌呤和鸟嘌呤的2-丙基和其他烷基衍生物、2-硫尿嘧啶、2-硫胸腺嘧啶和2-硫胞嘧啶、5-卤代尿嘧啶和胞嘧啶、5-丙炔基尿嘧啶和胞嘧啶、6-偶氮尿嘧啶、胞嘧啶和胸腺嘧啶、5-尿嘧啶(假尿嘧啶)、4-硫尿嘧啶、8-卤代、8-氨基、8-巯基、8-硫烷基、8-羟基和其他8-取代的腺嘌呤和鸟嘌呤、5-卤代具体地5-溴、5-三氟甲基和其他5-取代的尿嘧啶和胞嘧啶、7-甲基鸟嘌呤(methylquanine)和7-甲基腺嘌呤、8-氮杂鸟嘌呤和8-氮杂腺嘌呤、7-脱氮杂鸟嘌呤和7-脱氮杂腺嘌呤以及3-脱氮杂鸟嘌呤和3-脱氮杂腺嘌呤。
此外,核苷酸包括公开于以下文献中的核苷酸:美国专利第3,687,808号、“高分子科学和工程的简明百科全书(The Concise Encyclopedia of Polymer Science AndEngineering)”,858-859页,Kroschwitz, J.I.,编辑,John Wiley & Sons, 1990、Englisch等,'Angewandle Chemie, International Edition', 1991, 30, 613页、和Sanghvi, Y.S., 第15章,“反义研究和应用(Antisense Research and Applications)”,289-302页,Crooke, S.T.和Lebleu, B. ea., CRC Press, 1993。这些核苷酸中的某些对于增加本发明的寡聚化合物的结合亲和力特别地有用。这些包括5-取代嘧啶、6-氮杂嘧啶和N-2、N-6和0-6取代的嘌呤,包括2-氨丙基腺嘌呤、5-丙炔基尿嘧啶和5-丙炔基胞嘧啶。已显示5-甲基胞嘧啶取代增加核酸双链体的稳定性达0.6-1.2℃ (Sanghvi, Y.S., Crooke,S.T.和Lebleu, B.,编辑,“反义研究和应用”, CRC Press, Boca Raton, 1993,276-278页)且为目前优选的碱基取代,甚至更特别地当与2’-O甲氧基乙基糖修饰组合时。
教导制备上述修饰核苷酸以及其他修饰核苷酸的代表性的美国专利包括但不限于,美国专利第3,687,808、以及4,845,205、5,130,302、5,134,066、5,175, 273、5, 367,066、5,432,272、5,457,187、5,459,255、5,484,908、5,502,177、5,525,711、5,552,540、5,587,469、5,596,091、5,614,617、5,750,692和5,681,941号,每个通过引用结合于本文中。
本发明的寡核苷酸的另一种修饰涉及使所述寡核苷酸与一种或多种部分或缀合物化学连接,该部分或缀合物增强所述寡核苷酸的活性、细胞分布或细胞摄取。
这类部分包括但不限于,脂质部分(例如胆固醇部分)(Letsinger等,(1989)Proc.Natl. Acad. Sci. USA, 86, 6553-6556)、胆酸(Manoharan等,(1994) Bioorg. Med.Chem. Let., 4, 1053-1060)、硫醚(例如,己基-S-三苯甲基硫醇) (Manoharan等,(1992)Ann. N. Y. Acad. Sci., 660, 306-309;Manoharan等,(1993) Bioorg. Med. Chem.Let., 3, 2765-2770)、硫代胆固醇(Oberhauser等,(1992) Nucl. Acids Res., 20, 533-538)、脂族链(例如,十二烷二醇或十一烷基残基) (Kabanov等,(1990) FEBS Lett., 259,327-330;Svinarchuk等,(1993) Biochimie 75, 49-54)、磷脂(例如,二-十六烷基-消旋-甘油或1,2-二-O-十六烷基-消旋-甘油-3-H-膦酸三乙铵) (Manoharan等,(1995)Tetrahedron Lett., 36, 3651-3654;Shea等,(1990) Nucl. Acids Res., 18, 3777-3783)、聚胺或聚乙二醇链(Mancharan等,(1995) Nucleosides & Nucleotides, 14, 969-973)、或TTP触角乙酸(Manoharan等,(1995) Tetrahedron Lett., 36, 3651-3654)、棕榈基部分(Mishra等,(1995) Biochim. Biophys. Acta, 1264, 229-237)、或十八胺或己基氨基-羰基-t羟胆固醇部分(Crooke等,(1996) J. Pharmacol. Exp. Ther., 277, 923-937)。
教导制备这类寡核苷酸缀合物的代表性的美国专利包括但不限于,美国专利第4,828,979、4,948,882、5,218,105、5,525,465、5,541,313、5,545,730、5,552, 538、5,578,717、5,580,731、5,580,731、5,591,584、5,109,124、5,118,802、5,138,045、5,414,077、5,486, 603、5,512,439、5,578,718、5,608,046、4,587,044、4,605,735、4,667,025、4,762,779、4,789,737、4,824,941、4,835,263、4,876,335、4,904,582、4,958,013、5,082, 830、5,112,963、5,214,136、5,082,830、5,112,963、5,214,136、5, 245,022、5,254,469、5,258,506、5,262,536、5,272,250、5,292,873、5,317,098、5,371,241、5,391, 723、5,416,203、5,451,463、5,510,475、5,512,667、5,514,785、5, 565,552、5,567,810、5,574,142、5,585,481、5,587,371、5,595,726、5,597,696、5,599,923、5,599, 928和5,688,941号,每个通过引用结合于本文中。
药物开发:本发明的化合物也可应用于药物开发和靶标验证的领域。本发明包括本文所鉴定的化合物和优选的靶区段在阐明存在于三重四脯氨酸(TTP)多核苷酸和疾病状态、表型或病况之间的关系的药物开发努力中的应用。这些方法包括检测或调节三重四脯氨酸(TTP)多核苷酸,包括使本发明的化合物与样品、组织、细胞或生物体接触,在处理后的某个时间测定三重四脯氨酸(TTP)多核苷酸的核酸或蛋白水平和/或相关的表型或化学终末点,以及任选将该测定值与未处理样品或与用本发明的另一种化合物处理的样品比较。这些方法也可与其他试验平行或组合进行以确定未知基因的功能用于靶标验证过程,或确定特定基因产物作为用于治疗或预防特定疾病、病况或表型的靶标的有效性。
评价基因表达的增量调节或抑制:
外源核酸到宿主细胞或生物体中的转移可通过直接检测细胞或生物体中核酸的存在情况来评价。这类检测可通过本领域众所周知的数种方法来完成。例如,外源核酸的存在情况可通过DNA印迹或通过聚合酶链式反应(PCR)技术使用以下引物来检测,该引物特异地扩增与所述核酸相关的核苷酸序列。外源核酸的表达也可使用包括基因表达分析在内的常规方法来测定。例如,由外源核酸产生的mRNA可使用RNA印迹和反转录PCR(RT-PCR)来检测和定量。
来自外源核酸的RNA表达也可通过测定酶活性或报道蛋白活性来检测。例如,反义调节活性可根据靶核酸表达的减少或增加间接地测定,靶核酸表达作为外源核酸正在产生效应物RNA的指示。基于序列保守性,可设计和使用引物来扩增靶基因的编码区。最初,可使用来自每个基因的最高表达的编码区来建立模型对照基因,但任何编码或非编码区均可使用。每个对照基因通过将每个编码区插入报道基因编码区和其聚腺苷酸信号之间来装配。这些质粒可产生在基因的上游部分具有报道基因以及在3’非编码区中具有潜在RNAi靶标的mRNA。各个反义寡核苷酸的有效性可通过调节报道基因来测定。可用于本发明的方法中的报道基因包括乙酰羟酸合酶(AHAS)、碱性磷酸酶(AP)、β半乳糖苷酶(LacZ)、β葡糖醛酸酶(GUS)、氯霉素乙酰转移酶(CAT)、绿色荧光蛋白(GFP)、红色荧光蛋白(RFP)、黄色荧光蛋白(YFP)、青色荧光蛋白(CFP)、辣根过氧化物酶(HRP)、萤光素酶(Luc)、胭脂碱合酶(NOS)、章鱼碱合酶(OCS),以及其衍生物。多重选择标记为可利用的,其赋予对氨苄青霉素、博来霉素、氯霉素、庆大霉素、潮霉素、卡那霉素、林可霉素、甲氨蝶呤、草丁膦(phosphinothricin)、嘌呤霉素和四环素的抗性。确定报道基因调节的方法为本领域众所周知的,包括但不限于,荧光法(例如荧光光谱法、荧光激活细胞分选术(FACS)、荧光显微法)、抗生素抗性测定。
TTP蛋白和mRNA表达可使用本领域技术人员已知和本文别处所描述的方法测定。例如,免疫测定法(例如ELISA)可用来测定蛋白水平。用于ELISA的TTP抗体可市购,例如,从Santa Cruz Biotechnology, (Santa Cruz, CA) (Minneapolis, MN), Abcam,Cambridge, MA。
在实施方案中,使用本发明反义寡核苷酸处理的样品(例如,体内或体外细胞或组织)中的TTP表达(例如,mRNA或蛋白)通过与对照样品中的TTP表达相比较来评价。例如,蛋白或核酸表达可使用本领域技术人员已知的方法,与模拟处理或未处理样品中的蛋白或核酸表达相比较。或者,与用对照反义寡核苷酸(例如,具有已改变或不同序列的反义寡核苷酸)处理的样品的比较可根据所需信息来进行。在另一个实施方案中,可将已处理样品对比未处理样品在TTP蛋白或核酸表达方面的差异,与已处理样品对比未处理样品在不同核酸(包括研究者认为适当的任何标准,例如,持家基因)表达方面的差异相比较。
可将观察到的差异根据需要例如以比例或分数的形式表达,用于与对照的比较。在实施方案中,TTP mRNA或蛋白水平,在用本发明反义寡核苷酸处理的样品中,相对于未处理样品或用对照核酸处理的样品增加至约1.25倍-约10倍或更多或减少至约1/1.25-约1/10或更少。在实施方案中,TTP mRNA或蛋白水平增加或减少至至少约1.25倍、至少约1.3倍、至少约1.4倍、至少约1.5倍、至少约1.6倍、至少约1.7倍、至少约1.8倍、至少约2倍、至少约2.5倍、至少约3倍、至少约3.5倍、至少约4倍、至少约4.5倍、至少约5倍、至少约5.5倍、至少约6倍、至少约6.5倍、至少约7倍、至少约7.5倍、至少约8倍、至少约8.5倍、至少约9倍、至少约9.5倍、或至少约10倍或更多。
试剂盒、研究试剂、诊断和治疗
本发明的化合物可用于诊断、治疗和预防,并作为研究试剂和试剂盒的组分。此外,能够灵敏特异地抑制基因表达的反义寡核苷酸,常常被普通技术人员用于阐明特定基因的功能或区分生物途径的各个成员之间的功能。
对于用于试剂盒和诊断和各种生物系统,本发明的化合物(单独的或与其他化合物或治疗剂组合)可用作在差异和/或组合分析中的工具,以阐明在细胞和组织内表达的基因的一部分或全部互补序列的表达模式。
本文所用的术语“生物系统”或“系统”定义为表达或使得能够表达三重四脯氨酸(TTP)基因产物的任何生物体、细胞、细胞培养物或组织。这些包括但不限于人、转基因动物、细胞、细胞培养物、组织、异种移植物、移植物及其组合。
作为一个非限制性实例,将在用一种或多种反义化合物处理的细胞或组织内的表达模式与未用反义化合物处理的对照细胞或组织相比较,并针对基因表达的差异水平分析产生的模式,因为它们有关于,例如,所检测基因的疾病相关、信号传导途径、细胞定位、表达水平、大小、结构或功能。这些分析可对受刺激或未受刺激的细胞以及在影响表达模式的其他化合物存在或不存在时进行。
本领域已知的基因表达分析方法的实例包括DNA阵列或微阵列(Brazma和Vilo,(2000) FEBS Lett., 480, 17-24;Celis等,(2000) FEBS Lett., 480, 2-16)、SAGE(基因表达的系列分析) (Madden等,(2000) Drug Discov. Today, 5, 415- 425)、READS(已消化cDNA的限制酶扩增) (Prashar和Weissman, (1999) Methods Enzymol., 303, 258-72)、TOGA(总基因表达分析) (Sutcliffe等,(2000) Proc. Natl. Acad. Sci. U.S.A.,97, 1976-81)、蛋白质阵列和蛋白质组学(Celis等,(2000) FEBS Lett., 480, 2-16;Jungblut等,Electrophoresis, 1999, 20, 2100-10)、已表达序列标志(EST)测序(Celis等,FEBS Lett., 2000, 480, 2-16; Larsson等,J. Biotechnol., 2000, 80, 143-57)、消减(subtractive)RNA指纹法(SuRF) (Fuchs等,(2000) Anal. Biochem. 286, 91-98;Larson等,(2000) Cytometry 41, 203-208)、消减克隆、差异显示(DD) (Jurecic和Belmont, (2000) Curr. Opin. Microbiol. 3, 316-21)、比较基因组杂交(Carulli等,(1998) J. Cell Biochem. Suppl., 31, 286-96)、FISH(荧光原位杂交)技术(Going和Gusterson, (1999) Eur. J. Cancer, 35, 1895-904)和质谱分析法(To, Comb. (2000)Chem. High Throughput Screen, 3, 235-41)。
本发明的化合物对于研究和诊断而言为有用的,因为这些化合物与编码三重四脯氨酸(TTP)的核酸杂交。例如,作为有效的三重四脯氨酸(TTP)调节剂以本文公开的这类效率和这类条件下杂交的寡核苷酸,在有利于基因扩增或检测的条件下分别为有效的引物或探针。这些引物和探针可用于需要对编码三重四脯氨酸(TTP)的核酸分子特异检测的方法中,和可用于扩增所述核酸分子,以用于检测或用于进一步研究三重四脯氨酸(TTP)。本发明的反义寡核苷酸(具体地,引物和探针)与编码三重四脯氨酸(TTP)的核酸的杂交,可通过本领域已知的方法来检测。这类方法可包括使酶与所述寡核苷酸缀合、放射性标记所述寡核苷酸或任何其他适当的检测方法。也可制备使用这类检测方法来检测样品中三重四脯氨酸(TTP)水平的试剂盒。
反义物的特异性和灵敏性也由本领域技术人员掌握用于治疗用途。已将反义化合物在动物(包括人)的疾病状态的治疗中用作治疗部分。反义寡核苷酸药物已安全和有效地施用给人且许多临床试验目前正在进行。因此确立的是,反义化合物可为有用的治疗形式,可将其经配置以在用于治疗细胞、组织和动物、尤其是人的治疗方案中有用。
对于治疗而言,将怀疑具有可通过调节三重四脯氨酸(TTP)多核苷酸的表达来治疗的疾病或障碍的动物(优选人),通过施用依照本发明的反义化合物来治疗。例如,在一个非限制性实施方案中,所述方法包括给需要治疗的动物施用治疗上有效量的三重四脯氨酸(TTP)调节剂的步骤。本发明的三重四脯氨酸(TTP)调节剂有效地调节三重四脯氨酸(TTP)的活性或调节三重四脯氨酸(TTP)蛋白的表达。在一个实施方案中,动物中三重四脯氨酸(TTP)的活性或表达与对照相比抑制了约10%。优选地,将动物中三重四脯氨酸(TTP)的活性或表达抑制约30%。更优选地,将动物中三重四脯氨酸(TTP)的活性或表达抑制50%或更多。因此,与对照相比,寡聚化合物将三重四脯氨酸(TTP) mRNA的表达调节至少10%、至少50%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%、或100%。
在一个实施方案中,与对照相比,在动物中三重四脯氨酸(TTP)的活性或表达增加约10%。优选地,在动物中三重四脯氨酸(TTP)的活性或表达增加约30%。更优选地,在动物中三重四脯氨酸(TTP)的活性或表达增加50%或更多。因此,与对照比较,寡聚化合物使三重四脯氨酸(TTP) mRNA的表达调节至少10%、至少50%、至少25%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%、至少99%或100%。
例如,三重四脯氨酸(TTP)表达的下降可在动物的血清、血液、脂肪组织、肝脏或任何其他体液、组织或器官中测定。优选地,包含于待分析的所述液体、组织或器官之内的细胞包含编码三重四脯氨酸(TTP)肽的核酸分子和/或三重四脯氨酸(TTP)蛋白本身。
本发明的化合物可通过向合适的药学上可接受的稀释剂或载体中添加有效量的化合物来用于药物组合物。本发明的化合物和方法的应用也可为预防上有用的。
缀合物
本发明的寡核苷酸的另一种修饰涉及以化学方法将一种或多种增强寡核苷酸的活性、细胞分布或细胞摄取的部分或缀合物与寡核苷酸连接。这些部分或缀合物可包含与官能团(例如伯羟基或仲羟基)共价结合的缀合基团。本发明的缀合基团包括嵌入剂、报道分子、聚胺、聚酰胺、聚乙二醇、聚醚、增强寡聚体药效学特性的基团,以及增强寡聚体药代动力学特性的基团。典型的缀合基团包括胆固醇、脂质、磷脂、生物素、吩嗪、叶酸、菲啶、蒽醌、吖啶、荧光黄、罗丹明、香豆素和染料。增强药效学特性的基团,在本发明的背景中,包括改善摄取、增强对降解的抗性和/或加强与靶核酸的序列特异性杂交的基团。增强药代动力学特性的基团,在本发明的背景中,包括改善本发明的化合物的摄取、分布、代谢或分泌的基团。代表性的缀合基团在提交于1992年10月23日的国际专利申请第PCT/US92/09196号和美国专利第6,287,860号中公开,所述文献通过引用结合于本文中。缀合部分包括但不限于,脂质部分(例如胆固醇部分)、胆酸、硫醚(例如,己基-5-三苯甲基硫醇)、硫代胆固醇、脂族链(例如,十二烷二醇或十一烷基残基)、磷脂(例如,二-十六烷基-消旋-甘油或1,2-二-O-十六烷基-消旋-甘油-3-H-膦酸三乙铵)、聚胺或聚乙二醇链、或TTP触角乙酸、棕榈基部分、或十八胺或己基氨基-羰基-羟胆固醇部分。也可将本发明的寡核苷酸与活性药物物质缀合,例如,阿司匹林、华法林、保泰松、布洛芬、舒洛芬、芬布芬、酮洛芬、(S)-(+)普拉洛芬、卡洛芬、丹酰肌氨酸、2,3,5-三碘苯甲酸、氟芬那酸、亚叶酸、苯并噻二嗪、氯噻嗪、二氮杂、吲哚美辛(indomethicin)、巴比妥酸盐、头孢菌素、磺胺类药物、抗糖尿病药、抗菌剂或抗生素。
教导制备这类寡核苷酸缀合物的代表性的美国专利包括但不限于,美国专利第4,828,979、4,948,882、5,218,105、5,525,465、5,541,313、5,545,730、5,552,538、5,578,717、5,580,731、5,580,731、5,591,584、5,109,124、5,118,802、5,138,045、5,414,077、5,486,603、5,512,439、5,578,718、5,608,046、4,587,044、4,605,735、4,667,025、4,762,779、4,789,737、4,824,941、4,835,263、4,876,335、4,904,582、4,958,013、5,082,830、5,112,963、5,214,136、5,082,830、5,112,963、5,214,136、5,245,022、5,254,469、5,258,506、5,262,536、5,272,250、5,292,873、5,317,098、5,371,241、5,391,723、5,416,203、5,451,463、5,510,475、5,512,667、5,514,785、5,565,552、5,567,810、5,574,142、5,585,481、5,587,371、5,595,726、5,597,696、5,599,923、5,599,928和5,688,941号。
制剂
本发明的化合物也可与其他分子、分子结构或化合物的混合物混合、封装、缀合或其他方式缔合,作为例如,脂质体、受体靶向分子、口服的、直肠的、局部的或其他制剂,用于有助于摄取、分布和/或吸收。教导制备这类摄取、分布和/或吸收辅助制剂的代表性的美国专利包括但不限于,美国专利第5,108,921、5,354,844、5,416,016、5,459,127、5,521,291、5,543,165、5,547,932、5,583,020、5,591,721、4,426,330、4,534,899、5,013,556、5,108,921、5,213,804、5,227,170、5,264,221、5,356,633、5,395,619、5,416,016、5,417,978、5,462,854、5,469,854、5,512,295、5,527,528、5,534,259、5,543,152、5,556,948、5,580,575和5,595,756号,每个通过引用结合于本文中。
尽管,反义寡核苷酸不需要在载体的情况中施用以便调节靶表达和/或功能,但是本发明的实施方案涉及用于反义寡核苷酸表达的表达载体构建体,包括启动子、杂合启动子基因序列并且拥有强组成型启动子活性,或可在所需情况下诱导的启动子活性。
在一个实施方案中,本发明实施涉及用适合的核酸递送系统施用至少一种前述反义寡核苷酸。在一个实施方案中,该系统包含与多核苷酸可操作连接的非病毒载体。这类非病毒载体的实例包括单独的寡核苷酸(例如,SEQ ID NO: 6-10中的任何一个或多个)或与适合的蛋白、多糖或脂质制剂组合的寡核苷酸。
其他适合的核酸递送系统包括病毒载体,典型地来自腺病毒、腺病毒伴随病毒(AAV)、依赖辅助病毒的腺病毒、逆转录病毒或仙台病毒-脂质体(HVJ)复合体中的至少一种的序列。优选地,所述病毒载体包含与多核苷酸可操作连接的强真核启动子,例如,巨细胞病毒(CMV)启动子。
另外优选的载体包括病毒载体、融合蛋白和化学缀合物。逆转录病毒载体包括莫洛尼鼠白血病病毒和基于HIV的病毒。一种优选的基于HIV的病毒载体包括至少两种载体,其中gag基因和pol基因来自HIV基因组而env基因来自另一种病毒。DNA病毒载体为优选的。这些载体包括痘病毒载体(例如正痘病毒或禽痘病毒载体)、疱疹病毒载体(例如单纯疱疹I病毒(HSV)载体[Geller, A.I.等,(1995) J. Neurochem, 64: 487;Lim, F. 等,载于DNA克隆:哺乳动物系统(DNA Cloning: Mammalian Systems), D. Glover,编辑,(OxfordUniv. Press, Oxford England) (1995);Geller, A.I. 等,(1993) Proc Natl. Acad.Sci.: U.S.A.:90 7603;Geller, A.I. 等,(1990) Proc Natl. Acad. Sci USA: 87:1149])、腺病毒载体(LeGal LaSalle等,Science, 259:988 (1993);Davidson等,(1993)Nat. Genet. 3: 219;Yang等,(1995) J. Virol. 69: 2004)和腺伴随病毒载体(Kaplitt,M.G. 等,(1994) Nat. Genet. 8:148)。
本发明的反义化合物包括任何药学上可接受的盐、酯、或这类酯的盐、或任何其他化合物,其在施用给动物包括人后,能够提供(直接地或间接地)生物学活性的代谢物或其残留物。
术语“药学上可接受的盐”是指本发明化合物的生理上和药学上可接受的盐:即,保留母体化合物的所需生物活性且不对其赋予非所需的毒理学作用的盐。对于寡核苷酸而言,药学上可接受的盐的优选实例和其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。
本发明也包括包含本发明的反义化合物的药物组合物和制剂。本发明的药物组合物可以以若干方式来施用,这取决于是否需要局部或全身治疗以及待治疗的区域。施用可为局部的(包括眼的和至黏膜包括阴道和直肠递送)、肺的(例如,通过吸入或吹入散剂或气雾剂,包括通过喷雾器)、气管内的、鼻内的、表皮的和经皮的、口服的或胃肠外的。胃肠外施用包括静脉内、动脉内、皮下、腹膜内或肌肉注射或输注;或颅内(例如,鞘内或心室内)施用。
对于治疗中枢神经系统中的组织而言,可通过例如注射或输注进入脑脊髓液进行施用。施用反义RNA进入脑脊髓液已在例如美国专利申请公开第2007/0117772号,“Methodsfor slowing familial ALS disease progression (减缓家族性ALS疾病进展的方法)”中描述,该申请通过引用以其整体结合于本文中。
如果意图将本发明的反义寡核苷酸施用给中枢神经系统中的细胞,可与一种或多种能够促进主题反义寡核苷酸渗透穿过血脑屏障的物质一起施用。注射可在例如内嗅皮质或海马中进行。通过施用腺病毒载体递送神经营养因子至肌肉组织中的运动神经元描述于,例如,美国专利第6,632,427号,“Adenoviral-vector-mediated gene transfer intomedullary motor neurons (腺病毒载体介导基因转移进入髓质运动神经元)”,其通过引用结合于本文中。直接递送载体至脑(例如,纹状体、丘脑、海马或黑质)为本领域已知且描述于例如美国专利第6,756,523号,“Adenovirus vectors for the transfer of foreigngenes into cells of the central nervous system particularly in brain(用于转移外源基因进入中枢神经系统细胞(具体地脑中)的腺病毒载体)”,其通过引用结合于本文中。施用可快速,如通过注射,或在一段时间内进行,如通过缓慢输注或施用缓释制剂。
主题反义寡核苷酸也可与提供所需药学或药效学特性的物质连接或缀合。例如,反义寡核苷酸可与本领域已知的促进渗透或转运穿过血脑屏障的任何物质(例如转铁蛋白受体的抗体)偶联,并通过静脉注射施用。反义化合物可与病毒载体连接,例如,使反义化合物更有效和/或增加反义化合物转运穿过血脑屏障的病毒载体。渗透性血脑屏障破坏也可通过例如输注糖或氨基酸来完成,所述糖包括但不限于,内消旋赤藓醇、木糖醇、D(+)半乳糖、D(+)乳糖、D(+)木糖、卫矛醇、肌醇、L(-)果糖、D(-)甘露醇、D(+)葡萄糖、D(+)阿拉伯糖、D(-)阿拉伯糖、纤维二糖、D(+)麦芽糖、D(+)蜜三糖、L(+)鼠李糖、D(+)蜜二糖、D(-)核糖、侧金盏糖醇、D(+)阿拉伯糖醇、L(-)阿拉伯糖醇、D(+)岩藻糖、L(-)岩藻糖、D(-)来苏糖、L(+)来苏糖和L(-)来苏糖,所述氨基酸包括但不限于,谷氨酰胺、赖氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、甘氨酸、组氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、缬氨酸和牛磺酸。用于增强血脑屏障渗透的方法和材料描述于,例如,美国专利第4,866,042号,“Method for the delivery of genetic material across theblood brain barrier(用于递送遗传物质穿过血脑屏障的方法)”,第6,294,520号,“Material for passage through the blood-brain barrier(用于通过血脑屏障的材料)”,和第6,936,589号,“Parenteral delivery systems (胃肠外递送系统)”,全部通过引用以其整体结合于本文中。
主题反义化合物也可与其他分子、分子结构或化合物的混合物混合、封装、缀合或以其他方式缔合,作为例如,脂质体、受体靶向分子、口服的、直肠的、局部的或其他制剂,用于有助于摄取、分布和/或吸收。例如,阳离子脂质可包含在制剂中以促进寡核苷酸摄取。一种显示出促进摄取的这类组合物为LIPOFECTIN (可从GIBCO-BRL, Bethesda, MD获得)。
认为带有至少一个2’-O-甲氧基乙基修饰的寡核苷酸对于口服施用而言为特别有用的。用于局部施用的药物组合物和制剂可包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体和散剂。常规药物载体、水性、粉末或油性基质、增稠剂等可为必要的或所需的。包被的避孕套、手套等也可为有用的。
可适宜地以单位剂型存在的本发明药物制剂,可根据药学工业中众所周知的常规技术来制备。这类技术包括使活性成分与药物载体或赋形剂组合的步骤。一般而言,制剂如下制备:通过使活性成分与液体载体或细碎的固体载体或两者均匀和紧密地组合,随后在需要时使产物成形。
可将本发明的组合物制成任何许多可能剂型,例如但不限于,片剂、胶囊剂、凝胶胶囊、液体糖浆、软凝胶、栓剂和灌肠剂。也可将本发明的组合物在水性、非水性或混合介质中制成混悬剂。水性混悬剂可进一步包含增加混悬剂粘度的物质,包括例如羧甲基纤维素钠、山梨醇和/或葡聚糖。所述混悬剂也可包含稳定剂。
本发明的药物组合物包括但不限于,溶液剂、乳剂、泡沫剂和含脂质体的制剂。本发明的药物组合物和制剂可包含一种或多种渗透促进剂、载体、赋形剂或其他活性或非活性成分。
乳剂典型地为一种液体以通常直径超过0.1 μm的液滴形式分散在另一种液体中的非均质体系。乳剂可包含除分散相之外的其他组分,以及可作为在水相、油相中的溶液或其本身作为单独相存在的活性药物。将微乳液包括为本发明的一个实施方案。乳剂及其使用为本领域众所周知的且进一步描述于美国专利第6,287,860号中。
本发明的制剂包括脂质体制剂。本发明所用的术语“脂质体”意为由排列在一个或多个球形双层中的两亲脂质组成的囊泡。脂质体为具有由亲脂材料形成的膜和包含待递送组合物的水性内部的单层或多层囊泡。阳离子脂质体为带正电的脂质体,认为其与带负电的DNA分子相互作用以形成稳定的复合体。认为pH敏感的或带负电的脂质体诱捕DNA而不是与其复合。阳离子和非阳离子脂质体均已用来递送DNA到细胞。
脂质体也包括“空间上稳定的”脂质体,该术语如本文所用是指包含一种或多种特化脂质的脂质体。当掺入到脂质体中时,这些特化脂质给脂质体带来相对于缺乏这类特化脂质的脂质体增长的循环生命期。空间上稳定的脂质体的实例为以下脂质体,其中脂质体形成囊泡的脂质部分的部分包含一种或多种糖脂或衍生有一种或多种亲水聚合物,例如聚乙二醇(PEG)部分。脂质体及其使用进一步描述于美国专利第6,287,860号中。
本发明的药物制剂和组合物也可包含表面活性剂。表面活性剂在药物产品、制剂和乳剂中的使用为本领域众所周知的。表面活性剂及其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。
在一个实施方案中,本发明使用各种渗透促进剂来实现核酸特别是寡核苷酸的有效递送。除了有助于非亲脂性药物穿过细胞膜的扩散之外,渗透促进剂还增加亲脂性药物的渗透性。可将渗透促进剂归类为属于五大类的一种,五大类即表面活性剂、脂肪酸、胆汁盐、螯合剂和非螯合非表面活性剂。渗透促进剂及其使用进一步描述于美国专利第6,287,860号,其通过引用结合于本文中。
本领域的技术人员将认识到,根据其预期用途(即给药途径)来常规地设计制剂。
用于局部给药的优选制剂包括以下制剂,其中本发明寡核苷酸与局部递送剂(例如,脂质、脂质体、脂肪酸、脂肪酸酯、甾类化合物、螯合剂和表面活性剂)混合。优选的脂质和脂质体包括中性的(例如二油酰基-磷脂酰DOPE乙醇胺、二肉豆蔻酰基磷脂酰胆碱DMPC、二硬脂酰基磷脂酰胆碱)、阴性的(例如二肉豆蔻酰基磷脂酰甘油DMPG)和阳离子的(例如二油酰基四甲基氨丙基DOTAP和二油酰基-磷脂酰基乙醇胺DOTMA)。
对于局部或其他给药而言,可将本发明的寡核苷酸封装在脂质体内或可与其(特别是与阳离子脂质体)形成复合体。或者,可将寡核苷酸与脂质(特别是阳离子脂质)复合。优选的脂肪酸和酯类、其药学上可接受的盐以及它们的使用进一步描述于美国专利第6,287,860号中。
用于口服给药的组合物和制剂包括散剂或颗粒剂、微粒、纳米粒子、在水或非水性介质中的混悬剂或溶液剂、胶囊剂、凝胶胶囊、小药囊、片剂或小片。增稠剂、矫味剂、稀释剂、乳化剂、分散助剂或粘合剂可为所需的。优选的口服制剂为以下制剂,其中将本发明的寡核苷酸与一种或多种渗透促进剂、表面活性剂和螯合剂协同施用。优选的表面活性剂包括脂肪酸和/或其酯或盐、胆汁酸和/或其盐。优选的胆汁酸/盐和脂肪酸及其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。还优选的为渗透促进剂的组合,例如脂肪酸/盐与胆汁酸/盐的组合。特别优选的组合为月桂酸的钠盐、癸酸和UDCA。另外的渗透促进剂包括聚氧化乙烯-9-月桂醚、聚氧化乙烯-20-鲸蜡醚。本发明的寡核苷酸可以以包括喷雾干燥颗粒的颗粒形式口服地递送,或络合以形成微米或纳米粒子。寡核苷酸络合剂及其使用进一步描述于美国专利第6,287,860号中,其通过引用结合于本文中。
用于胃肠外、鞘内或心室内给药的组合物和制剂可包括无菌水性溶液剂,其也可含有缓冲液、稀释剂和其他适合的添加剂,例如但不限于,渗透促进剂、载体化合物和其他药学上可接受的载体或赋形剂。
本发明的某些实施方案提供药物组合物,所述药物组合物包含一种或多种寡聚化合物和一种或多种其他通过非反义机制来起作用的化学治疗剂。这类化学治疗剂的实例包括但不限于癌症化学治疗药物,例如柔红霉素、道诺霉素、更生霉素、多柔比星、表柔比星、伊达比星、依索比星、博来霉素、马磷酰胺、异环磷酰胺、胞嘧啶阿拉伯糖苷、双氯乙基-亚硝基脲、白消安、丝裂霉素C、放线菌素D、光神霉素、泼尼松、羟孕酮、睾酮、他莫昔芬、达卡巴嗪、丙卡巴肼、六甲蜜胺、五甲蜜胺、米托蒽醌、安吖啶、苯丁酸氮芥、甲基环己基亚硝基脲、氮芥、美法仑、环磷酰胺、6-巯基嘌呤、6-巯鸟嘌呤、阿糖胞苷、5-氮杂胞苷、羟基脲、喷司他丁、4-羟基过氧环磷酰胺、5-氟尿嘧啶(5-FU)、5-氟脱氧尿苷(5-FUdR)、甲氨蝶呤(MTX)、秋水仙碱、泰素、长春新碱、长春碱、依托泊苷(VP-16)、三甲曲沙、伊立替康、拓泊替康、吉西他滨、替尼泊苷、顺铂和己烯雌酚(DES)。当与本发明的化合物一起使用时,这类化学治疗剂可单独地(例如,5-FU和寡核苷酸)、序贯地(例如,5-FU和寡核苷酸持续一段时间,接着MTX和寡核苷酸)、或与一种或多种其他的这类化学治疗剂组合(例如,5-FU、MTX和寡核苷酸,或5-FU、放射疗法和寡核苷酸)使用。抗炎药(包括但不限于非甾体抗炎药和皮质类固醇)和抗病毒药物(包括但不限于利巴韦林(ribivirin)、阿糖腺苷、阿昔洛韦和更昔洛韦)也可组合到本发明的组合物中。反义化合物和其他非反义药物的组合也在本发明的范围之内。两种或更多种组合的化合物可一起或序贯使用。
在另一个相关的实施方案中,本发明的组合物可包含靶向到第一核酸的一种或多种反义化合物(特别是寡核苷酸),以及靶向到第二核酸靶标的一种或多种其他反义化合物。例如,第一靶标可为三重四脯氨酸(TTP)的特定反义序列,第二靶标可为来自另一个核苷酸序列的区域。或者,本发明的组合物可包含靶向到相同三重四脯氨酸(TTP)核酸靶标的不同区域的两种或更多种反义化合物。本文举例说明了许多反义化合物的实例而其他的可选自本领域已知的适合化合物。两种或更多种组合化合物可一起或序贯使用。
给药:
认为治疗组合物的制剂和其随后的施用(给药)在本领域技术人员的技术之内。给药取决于要治疗的疾病状态的严重性和应答性,而疗程从数天持续到数月,或直到完成治愈或达到疾病状态的减轻。最佳给药方案可根据患者体内药物蓄积的测定来计算。普通技术人员可容易地确定最适剂量、给药方法和重复率。最适剂量可根据单独寡核苷酸的相对功效而不同,一般可基于发现在体外和体内动物模型中有效的EC50来评价。一般而言,剂量为0.01 μg-100 g/kg体重,且可每天、每周、每月或每年给药一次或多次,或甚至每2-20年一次。本领域普通技术人员可基于测定体液或组织中药物的停留时间和浓度来容易地评估给药的重复率。成功治疗之后,可能需要使患者进行维持疗法以预防疾病状态的复发,其中所述寡核苷酸以维持剂量来施用,范围为0.01 μg-100 g/kg体重,每天一次或多次到每20年一次。
在实施方案中,使用下列剂量的药物治疗患者,所述剂量为至少约1、至少约2、至少约3、至少约4、至少约5、至少约6、至少约7、至少约8、至少约9、至少约10、至少约15、至少约20、至少约25、至少约30、至少约35、至少约40、至少约45、至少约50、至少约60、至少约70、至少约80、至少约90、或至少约100 mg/kg体重。反义寡核苷酸的某些注射剂量描述于,例如,美国专利第7,563,884号,“Antisense modulation of PTP1B expression (PTP1B表达的反义调节)”,通过引用以其整体结合于本文中。
虽然上文已描述了本发明的各种实施方案,但是应理解的是,其仅以实例的方式提供,而并非限制。对公开的实施方案的许多改变可依照本文的公开内容来进行,而不会背离本发明的精神或范围。因此,本发明的广度和范围不应受到任何上述的实施方案所限制。
本文提及的所有文件都通过引用结合到本文中。本申请引用的所有出版物和专利文件都为所有目的而通过引用结合,引用程度如同单独地指出各个单独出版物或专利文件一样。至于申请人在本文件中对不同参考文献的引用,申请人并不承认任何具体参考文献对其发明而言为“现有技术”。本发明的组合物和方法的实施方案举例说明于下列实施例中。
实施例
下列非限制性的实施例用于举例说明本发明的经挑选的实施方案。应理解的是,所示组分的比例变化和要素备选对本领域的技术人员而言为显而易见的且在本发明的实施方案的范围之内。
实施例1:对三重四脯氨酸(TTP)的反义核酸分子和/或三重四脯氨酸(TTP)多核苷酸有义链特异的反义寡核苷酸的设计
如上指出的术语“对……特异的寡核苷酸”或“靶向……的寡核苷酸”是指具有以下序列的寡核苷酸,该序列(i)能够与靶向基因的一部分形成稳定的复合体,或(ii)能够与靶向基因mRNA转录物的一部分形成稳定的双链体。
适当寡核苷酸的挑选通过使用计算机程序来促进,该计算机程序自动比对核酸序列并指出同一性或同源性区域。这类程序用于比较例如通过搜索诸如GenBank等数据库或通过测序PCR产物而获得的核酸序列。来自一系列物种的核酸序列的比较允许挑选显示出物种之间适当同一性程度的核酸序列。在未测序基因的情况下,进行DNA印迹来确定在靶物种和其他物种的基因之间的同一性程度。通过在不同严格性程度下进行DNA印迹,如本领域众所周知的,可获得同一性的近似测量。这些程序允许挑选这样的寡核苷酸,其对在待控制的受试者中的靶核酸序列表现高度的互补性而对在其他物种中的相应核酸序列表现较低程度的互补性。本领域技术人员将认识到,在挑选用于本发明的适当的基因区域上具有相当大的自由。
反义化合物为“可特异杂交的”,如果所述化合物与靶核酸的结合干扰靶核酸的正常功能,导致功能和/或活性的调节,并且在要求特异性结合的条件下具有足够程度的互补性以避免所述反义化合物与非靶核酸序列的非特异性结合,所述条件即在体内测定或治疗处理情况中的生理条件下,以及其中测定在体外测定情况中进行的条件下。
本文所述的寡核苷酸的杂交特性可通过本领域已知的一种或多种体外测定法来确定。例如,本文所述的寡核苷酸的特性可通过使用解链曲线测定法确定靶天然反义物和潜在药物分子之间的结合强度来获得。
靶天然反义物和潜在药物分子(Molecule)之间的结合强度,可使用任何已建立的测定分子间相互作用强度的方法例如解链曲线测定法来评价。
解链曲线测定法确定这样的温度,在该温度下天然反义物/Molecule复合体发生从双链构象到单链构象的迅速转变。此温度被广泛认可为两个分子之间相互作用强度的可靠衡量。
解链曲线测定法可使用实际的天然反义RNA分子的cDNA拷贝或对应Molecule的结合位点的合成DNA或RNA核苷酸来进行。包含进行此测定的所有必需试剂的多种试剂盒为可得的(例如Applied Biosystems Inc. MeltDoctor试剂盒)。这些试剂盒包含含有双链DNA(dsDNA)结合染料(例如ABI HRM染料、SYBR Green、SYTO,等等)之一的适宜的缓冲溶液。dsDNA染料的特性为,其在游离形式几乎不发出荧光,但当与dsDNA结合时为高度荧光的。
为进行所述测定,将所述cDNA或相应寡核苷酸以由具体制造商的方案限定的浓度与Molecule混合。将所述混合物加热到95℃以解离所有预先形成的dsDNA复合体,然后缓慢冷却到室温或由试剂盒制造商确定的其他较低的温度以使DNA分子退火。随后将新形成的复合体缓慢加热到95℃,同时连续地收集由反应产生的荧光量的数据。荧光强度反比于反应中存在的dsDNA量。数据可使用与所述试剂盒相配的实时PCR仪器(例如ABI’s StepOnePlus Real Time PCR System或LightTyper仪器, Roche Diagnostics, Lewes, UK)来收集。
解链峰通过使用适当软件(例如LightTyper (Roche)或SDS DissociationCurve, ABI)针对温度(x-轴)绘制荧光关于温度的负导数(在y-轴上的-d(荧光)/dT)的图形来构建。分析数据以确定从dsDNA复合体迅速转变到单链分子的温度。此温度称为Tm且正比于两个分子之间的相互作用强度。典型地,Tm将超过40℃。
实施例2:TTP多核苷酸的调节
用反义寡核苷酸处理HepG2细胞
使来自ATCC的HepG2细胞(目录号HB-8065)在37℃和5% CO2下生长于生长培养基(MEM/EBSS (Hyclone目录号SH30024或Mediatech目录号MT-10-010-CV) +10% FBS(Mediatech目录号MT35- 011-CV)+青霉素/链霉素(Mediatech目录号MT30-002-CI))。试验的前一天将所述细胞以密度1.5 × 105/ml再接种到6孔板,并在37℃和5% CO2下培养。在试验当天将6孔板中的培养基换成新鲜的生长培养基。将所有反义寡核苷酸稀释到20 μM的浓度。将2 μl此溶液与400 μl Opti-MEM培养基(Gibco目录号31985-070)和4 μlLipofectamine 2000(Invitrogen目录号11668019)在室温下孵育20 min,然后施用到具有HepG2细胞的6孔板的每个孔。含有用2 μl水代替所述寡核苷酸溶液的类似混合物用于模拟转染的对照。在37℃和5% CO2下培养3-18 h后,将培养基换成新鲜的生长培养基。添加反义寡核苷酸48 h后,将培养基移出,并遵循制造商的说明书使用Promega的SV Total RNAIsolation System(目录号Z3105)或Qiagen的RNeasy Total RNA Isolation试剂盒(目录号74181)从细胞中提取RNA。如制造商的方案中所述,向使用Thermo Scientific的VersocDNA试剂盒(目录号AB1453B)或High Capacity cDNA Reverse Transcription Kit(目录号4368813)进行的反转录反应中添加600 ng RNA。将来自此反转录反应的cDNA用于通过使用ABI Taqman Gene Expression Mix(目录号4369510)和由ABI (Applied BiosystemsTaqman Gene Expression Assay:Hs00185658_m1,Applied Biosystems Inc., FosterCity CA)设计的引物/探针的实时PCR,来监控基因表达。使用下面的PCR循环:50℃,2 min;95℃,10 min;40个循环的(95℃,15秒;60℃,1 min),使用Mx4000热循环仪(Stratagene)。
用反义寡核苷酸处理后基因表达的倍数变化基于处理和模拟转染的样品之间18S-标准化的dCt值的不同来计算。
实时PCR结果显示,HepG2细胞中TTP mRNA水平在用针对TTP反义物Hs.702367设计的siRNA中的两种(CUR-0370和CUR-0372)、针对TTP反义物AL513578设计的两种siRNA(CUR-0368和CUR-0336)和针对BG012178 设计的一种siRNA (CUR-0364)处理后48 h显著增加(图1)。
尽管本发明已就一个或多个实现举例说明并描述,但在阅读和理解本说明书和附图后,本领域技术人员将想到等价改变和修饰。此外,虽然本发明的具体特征可能已就几个实现中的唯一一个公开,但这类特征可与其他实现的一个或多个其他特征组合,因为对于任何给定或具体应用而言可为所需和有利的。
本公开内容的摘要将允许读者快速确定本技术公开内容的性质。在理解以下的情况下将其提出:其将不用于解释或限制随附权利要求的范围或含义。
序列表
<110> OPKO CuRNA, Inc.
<120> 通过抑制针对TTP的天然反义转录物来治疗三重四脯氨酸(TTP)相关的疾病
<130> TTP
<150> US61/175,812
<151> 2009-05-06
<160> 15
<170> PatentIn version 3.5
<210> 1
<211> 1745
<212> DNA
<213> 智人
<300>
<308> NM_003407
<309> 2010-07-18
<313> (1)..(1745)
<400> 1
agcctgactt cagcgctccc actctcggcc gacacccctc atggccaacc gttacaccat 60
ggatctgact gccatctacg agagcctcct gtcgctgagc cctgacgtgc ccgtgccatc 120
cgaccatgga gggactgagt ccagcccagg ctggggctcc tcgggaccct ggagcctgag 180
cccctccgac tccagcccgt ctggggtcac ctcccgcctg cctggccgct ccaccagcct 240
agtggagggc cgcagctgtg gctgggtgcc cccaccccct ggcttcgcac cgctggctcc 300
ccgcctgggc cctgagctgt caccctcacc cacttcgccc actgcaacct ccaccacccc 360
ctcgcgctac aagactgagc tatgtcggac cttctcagag agtgggcgct gccgctacgg 420
ggccaagtgc cagtttgccc atggcctggg cgagctgcgc caggccaatc gccaccccaa 480
atacaagacg gaactctgtc acaagttcta cctccagggc cgctgcccct acggctctcg 540
ctgccacttc atccacaacc ctagcgaaga cctggcggcc ccgggccacc ctcctgtgct 600
tcgccagagc atcagcttct ccggcctgcc ctctggccgc cggacctcac caccaccacc 660
aggcctggcc ggcccttccc tgtcctccag ctccttctcg ccctccagct ccccaccacc 720
acctggggac cttccactgt caccctctgc cttctctgct gcccctggca cccccctggc 780
tcgaagagac cccaccccag tctgttgccc ctcctgccga agggccactc ctatcagcgt 840
ctgggggccc ttgggtggcc tggttcggac cccctctgta cagtccctgg gatccgaccc 900
tgatgaatat gccagcagcg gcagcagcct ggggggctct gactctcccg tcttcgaggc 960
gggagttttt gcaccacccc agcccgtggc agccccccgg cgactcccca tcttcaatcg 1020
catctctgtt tctgagtgac aaagtgactg cccggtcaga tcagctggat ctcagcgggg 1080
agccacgtct cttgcactgt ggtctctgca tggaccccag ggctgtgggg acttggggga 1140
cagtaatcaa gtaatcccct tttccagaat gcattaaccc actcccctga cctcacgctg 1200
gggcaggtcc ccaagtgtgc aagctcagta ttcatgatgg tgggggatgg agtgtcttcc 1260
gaggttcttg ggggaaaaaa aattgtagca tatttaaggg aggcaatgaa ccctctcccc 1320
cacctcttcc ctgcccaaat ctgtctccta gaatcttatg tgctgtgaat aataggcctt 1380
cactgcccct ccagttttta tagacctgag gttccagtgt ctcctggtaa ctggaacctc 1440
tcctgagggg gaatcctggt gctcaaatta ccctccaaaa gcaagtagcc aaagccgttg 1500
ccaaacccca cccataaatc aatgggccct ttatttatga cgactttatt tattctaata 1560
tgattttata gtatttatat atattgggtc gtctgcttcc cttgtatttt tcttcctttt 1620
tttgtaatat tgaaaacgac gatataatta ttataagtag actataatat atttagtaat 1680
atatattatt accttaaaag tctatttttg tgttttgggc atttttaaat aaacaatctg 1740
agtgt 1745
<210> 2
<211> 2559
<212> DNA
<213> 智人
<400> 2
cagcctgact tcagcgctcc cactctcggc cgacacccct catggccaac cgttacacca 60
tggatctgac tgccatctac gaggtgagtc cccgccgcac ggcatccccg gtacctgcat 120
gcctgagtcc gagtccccac ctctctagcg ccgcaaactc cagcccggga cgcttgcctc 180
ccttctccaa ctggggctcc ctagcgccgc gccctccagc ctggggcccc tgcctcccgc 240
tcagaccagc ttggtgattt ggaggtgaaa atggaacccg cgacacccgg ctcttcgctc 300
aaacatgggt ggggcggccc atgcaagtgg aaagtcggag aacttttctc agaccgaggc 360
tgcctggagg cggaagtggc ccccatacct ggctcacccc tagtcgttgc tgagggcgtg 420
gttttgcgcg gaggcgtctc tggggctgaa gtctcagggt ggggggatcc gacttctgtc 480
tctccagtcc ctgaccgtag agacagagaa ccctaaaacc gaagcaatcc ggacttccag 540
gtcaactttg cccggtttct ccagttgtga aactggagat cccgacgcgt gggtcatatc 600
cggggaggac aagagaccca aaattgggaa acagtggtgc gccctgactt cggggtcccc 660
ctcttggtcc agccggggaa gccgggattc ctgggtccct cgggataagg cctcggtggt 720
gggtaaactc agaacctcca actctgggtt cctggcatcc ggaacccagg ggtttctgcg 780
ggcgggtggg gctcaggcgg ggagcccaca aaccggcctg gcaagctcta gttccctgca 840
gctggggtgg ggcgtcgccc tgcattttca ggtgccttaa ccgacccatt tccgcagagc 900
ctcctgtcgc tgagccctga cgtgcccgtg ccatccgacc atggagggac tgagtccagc 960
ccaggctggg gctcctcggg accctggagc ctgagcccct ccgactccag cccgtctggg 1020
gtcacctccc gcctgcctgg ccgctccacc agcctagtgg agggccgcag ctgtggctgg 1080
gtgcccccac cccctggctt cgcaccgctg gctccccgcc tgggccctga gctgtcaccc 1140
tcacccactt cgcccactgc aacctccacc accccctcgc gctacaagac tgagctatgt 1200
cggaccttct cagagagtgg gcgctgccgc tacggggcca agtgccagtt tgcccatggc 1260
ctgggcgagc tgcgccaggc caatcgccac cccaaataca agacggaact ctgtcacaag 1320
ttctacctcc agggccgctg cccctacggc tctcgctgcc acttcatcca caaccctagc 1380
gaagacctgg cggccccggg ccaccctcct gtgcttcgcc agagcatcag cttctccggc 1440
ctgccctctg gccgccggac ctcaccacca ccaccaggcc tggccggccc ttccctgtcc 1500
tccagctcct tctcgccctc cagctcccca ccaccacctg gggaccttcc actgtcaccc 1560
tctgccttct ctgctgcccc tggcaccccc ctggctcgaa gagaccccac cccagtctgt 1620
tgcccctcct gccgaagggc cactcctatc agcgtctggg ggcccttggg tggcctggtt 1680
cggaccccct ctgtacagtc cctgggatcc gaccctgatg aatatgccag cagcggcagc 1740
agcctggggg gctctgactc tcccgtcttc gaggcgggag tttttgcacc accccagccc 1800
gtggcagccc cccggcgact ccccatcttc aatcgcatct ctgtttctga gtgacaaagt 1860
gactgcccgg tcagatcagc tggatctcag cggggagcca cgtctcttgc actgtggtct 1920
ctgcatggac cccagggctg tggggacttg ggggacagta atcaagtaat ccccttttcc 1980
agaatgcatt aacccactcc cctgacctca cgctggggca ggtccccaag tgtgcaagct 2040
cagtattcat gatggtgggg gatggagtgt cttccgaggt tcttggggga aaaaaaattg 2100
tagcatattt aagggaggca atgaaccctc tcccccacct cttccctgcc caaatctgtc 2160
tcctagaatc ttatgtgctg tgaataatag gccttcactg cccctccagt ttttatagac 2220
ctgaggttcc agtgtctcct ggtaactgga acctctcctg agggggaatc ctggtgctca 2280
aattaccctc caaaagcaag tagccaaagc cgttgccaaa ccccacccat aaatcaatgg 2340
gccctttatt tatgacgact ttatttattc taatatgatt ttatagtatt tatatatatt 2400
gggtcgtctg cttcccttgt atttttcttc ctttttttgt aatattgaaa acgacgatat 2460
aattattata agtagactat aatatattta gtaatatata ttattacctt aaaagtctat 2520
ttttgtgttt tgggcatttt taaataaaca atctgagtg 2559
<210> 3
<211> 970
<212> DNA
<213> 智人
<220>
<221> misc_feature
<222> (45)..(45)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (66)..(66)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (68)..(68)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (70)..(70)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (73)..(73)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (90)..(90)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (93)..(93)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (103)..(103)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (108)..(108)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (153)..(154)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (156)..(157)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (169)..(169)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (174)..(174)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (176)..(176)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (183)..(183)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (227)..(227)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (230)..(230)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (257)..(257)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (372)..(372)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (632)..(632)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (823)..(823)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (897)..(897)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (922)..(922)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (947)..(947)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (954)..(955)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (958)..(958)
<223> n是a, c, g或t
<400> 3
ataaagatca tattagaata aataaagtcg gtcataaata aaggncgcca ttggtttatg 60
ggtggngntn ggnaacgggt ttgggtactn gcntttgggg ggnaattngg gcgccagggt 120
tccccctcag ggggggttcc agtgaccagg ggnnanngga acctcaggnc tatnanaact 180
ggnggggcag tgaaggccta ttattcacag cacataagat tctaggngan agatttgggc 240
agggaagagg tgggggngag ggttcattgc ctcccttaaa tatgctacaa tttttttttc 300
ccccaagaac ctcggaaggc actccatccc ccaccatcat gaatactggg cttgcgcact 360
tgggggcctg cnccagcgtg aggtcagggg agtgggttaa tgcattctgg aaaaggggat 420
tacttgatta ctgtccccca agtccccaca gccctggggt ccatgcagag accacagtgc 480
aagagagcgt ggctccccgc tgagatccag ctgatctgac cgggcagtca ctttgtcact 540
cagaaacaga gatgcgattg aagatgggga gtcgccgggg ggctgccacg ggctggggtg 600
gtgcaaaaac tcccgcctcg aagacgggag antcagagcc ccccaggctg ctgccgctgc 660
tggcatattc atcagggtcg gatcccaggg actgtacaga gggggtccga accaggccac 720
ccaagggccc ccagacgctg ataggagtgg cccttcggca ggaggggcaa cagactgggg 780
gtggggtctc ttcgagccag ggggggtgcc aggggcagca ganaaggcag aggggtgaca 840
gtggaaggtc ccaggtggtg gtggggagct ggagggcgag aaggagctgg aggacangga 900
agggcgggcc aggctggtgg tngtggtgag gtccggcggc aaaaggnggg cggnnaanct 960
gatgctctgg 970
<210> 4
<211> 1117
<212> DNA
<213> 智人
<220>
<221> misc_feature
<222> (375)..(375)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1000)..(1000)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1016)..(1016)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1018)..(1018)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1030)..(1030)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1061)..(1061)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1065)..(1065)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1075)..(1075)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1086)..(1086)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (1088)..(1088)
<223> n是a, c, g或t
<400> 4
gtggggacgg aaacatcccg tccccgaccg cacccgcccg aagctgggtc aaggagccca 60
gcaggacggg agcgcggcgc ccccgacgcc cgggaactgg ctcccccggt tcccatctgg 120
tgacctcacc tggtcccacc ctttcaggtg aacggccagg cccggtgacg tcacttcctg 180
ccagaagcac ctctctccct cgctccgccc ttcacccaga cgctcgccaa tccgtgtgtg 240
gttccgagcc ggacttcatt tccccgaagc gtcgcggcct gaggagaccc gttgggtcct 300
cagcgtcttg gcggcagttg gtggaaccgg agcttcgagt ccgtccccgg tgctgcctgc 360
gcgttcacct gagtntcgct ggagctcttc tcgcccgccc acctcatctc aacccacttt 420
ccgcggggag cggcgccaag ctgggccttc ctcggatcag gcgtcccctg aagtcggcac 480
gcccctctgc gtcccccttc ggtcccgcta ggaccccgtc cgggctgccg tcgcctcgtc 540
gctatggcgc ccaccatcca gacccaggcc cagcgggagg atggccacag gccaattccc 600
accggactct gcctgagagg tctggagtgg tctgccgagt caagtactgc aatagcctcc 660
ctgatatccc cttcgacccc aagttcatca cctacccctt cgaccagaac agttcttcta 720
gatccagctg atgagaaact tttggaagag gagattcagg cccccaccag ctccaagaga 780
tcccagcagc acgcgaaggt ggtgccatgg atgcgaaaga cagagtacat ctccactgag 840
ttcaaccgtt atggcatctc caatgagaag cctgaggtca agattggggt ttctgtgaag 900
agcagtttac cgaggaagaa atatacaaag acagggatag ccagatcaca gccattgaga 960
agacttttga ggatgcccag aaatcaatct cacagcattn cagcaaaccc cgagtnanac 1020
cggtggaggn catgcctgtt ttcccagact ttaaaatgtg nttantcatg taccnaggtg 1080
atcttnanta aaccagcccc aaggaagagt ggggagc 1117
<210> 5
<211> 297
<212> DNA
<213> 智人
<220>
<221> misc_feature
<222> (184)..(185)
<223> n是a, c, g或t
<220>
<221> misc_feature
<222> (205)..(205)
<223> n是a, c, g或t
<400> 5
ggaatccgga ttgcttcggt tttagggttc tctgtctcta cggtcaggga ctggagagac 60
agaagtcgga tccccccacc ctgagacttc agccccagag acgcctccgc gcaaaaccac 120
gccctcagca acgactaggg gtgagccagg tatgggggcc gcttccgcct ccaggcagcc 180
tcgnngtctg agaaaacgtt ctccngactt tccacttgca tgggccgccc cacctatgtt 240
tgagcgaaga gccgggtgtc gcgggttcca ttttcacctc caaatcacca agctggt 297
<210> 6
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸
<400> 6
gacuucuguc ucuccagucc cugaccg 27
<210> 7
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸
<400> 7
guacucuguc uuucgcaucc auggcac 27
<210> 8
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸
<400> 8
aaucuugacc ucaggcuucu cauugga 27
<210> 9
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸
<400> 9
gauccgaccc ugaugaauau gccagca 27
<210> 10
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸
<400> 10
aucuucaauc gcaucucugu uucugag 27
<210> 11
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸 SEQ ID NO: 6的反向互补序列
<400> 11
gucagggacu ggagagacag aagtc 25
<210> 12
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸 SEQ ID NO: 7的反向互补序列
<400> 12
gccauggaug cgaaagacag aguac 25
<210> 13
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸 SEQ ID NO: 8的反向互补序列
<400> 13
caaugagaag ccugagguca agatt 25
<210> 14
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸 SEQ ID NO: 9的反向互补序列
<400> 14
cuggcauauu caucaggguc ggatc 25
<210> 15
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 反义寡核苷酸 SEQ ID NO: 10的反向互补序列
<400> 15
cagaaacaga gaugcgauug aagat 25
Claims (21)
1.如选自SEQ ID NOS:6-10的核酸序列所示的至少一种反义寡核苷酸在制备用于在体内或体外增量调节患者细胞或组织中三重四脯氨酸(TTP)多核苷酸的功能和/或表达的药物中的用途,其中所述药物与所述细胞或组织接触。
2.权利要求1的用途,其中三重四脯氨酸(TTP)的功能和/或表达在体内或体外相对于对照增加。
3.权利要求1的用途,其中所述至少一种反义寡核苷酸靶向三重四脯氨酸(TTP)多核苷酸的天然反义序列,所述多核苷酸选自SEQ ID NO: 3的核苷酸1-970、SEQ ID NO: 4的核苷酸1-1117 和SEQ ID NO: 5的核苷酸1-297。
4.权利要求1的用途,其中所述至少一种反义寡核苷酸靶向三重四脯氨酸(TTP)多核苷酸的编码和/或非编码核酸序列的天然反义寡核苷酸。
5.权利要求1的用途,其中所述至少一种反义寡核苷酸靶向天然反义寡核酸,所述天然反义寡核酸具有与三重四脯氨酸(TTP)多核苷酸重叠和/或非重叠的序列。
6.权利要求1的用途,其中所述至少一种反义寡核苷酸包含一种或多种选自以下的修饰:至少一种经修饰的糖部分、至少一种经修饰的核苷间键、至少一种经修饰的核苷酸及其组合。
7.权利要求6的用途,其中所述一种或多种修饰包括至少一种选自以下的经修饰糖部分:2’-O-甲氧基乙基修饰的糖部分、2’-甲氧基修饰的糖部分、2’-O-烷基修饰的糖部分、二环糖部分及其组合。
8.权利要求6的用途,其中所述一种或多种修饰包括至少一种选自以下的经修饰的核苷间键:硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、氨基乙酸酯、羧甲基酯及其组合。
9.权利要求6的用途,其中所述一种或多种修饰包括至少一种选自以下的经修饰核苷酸:肽核酸(PNA)、锁定核酸(LNA)、阿糖核酸(FANA)、其类似物、衍生物和组合。
10.一种长度为10-30个核苷酸的合成的、经修饰的寡核苷酸,所述寡核苷酸包含至少一种修饰,其中所述至少一种修饰选自:至少一种经修饰的糖部分;至少一种经修饰的核苷酸间键;至少一种经修饰的核苷酸及其组合;其中所述寡核苷酸如选自SEQ ID NOS:6-10的核酸序列所示,并且与正常对照相比,在体内或体外增量调节三重四脯氨酸(TTP)基因的功能和/或表达。
11.权利要求10的寡核苷酸,其中所述至少一种修饰包括选自以下的核苷酸间键:硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、氨基乙酸酯、羧甲基酯及其组合。
12.权利要求10的寡核苷酸,其中所述寡核苷酸包含至少一种硫代磷酸酯核苷酸间键。
13.权利要求10的寡核苷酸,其中所述寡核苷酸包含硫代磷酸酯核苷酸间键的骨架。
14.权利要求10的寡核苷酸,其中所述寡核苷酸包含至少一种经修饰的核苷酸,所述经修饰的核苷酸选自:肽核酸、锁定核酸(LNA)、其类似物、衍生物和组合。
15.权利要求10的寡核苷酸,其中所述寡核苷酸包含多种修饰,其中所述修饰包括选自以下的经修饰的核苷酸:硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、氨基乙酸酯、羧甲基酯及其组合。
16.权利要求10的寡核苷酸,其中所述寡核苷酸包含多种修饰,其中所述修饰包括选自以下的经修饰的核苷酸:肽核酸、锁定核酸(LNA)、其类似物、衍生物和组合。
17.权利要求10的寡核苷酸,其中所述寡核苷酸包含至少一种选自以下的经修饰的糖部分:2’-O-甲氧基乙基修饰的糖部分、2’-甲氧基修饰的糖部分、2’-O-烷基修饰的糖部分、二环糖部分及其组合。
18.权利要求10的寡核苷酸,其中所述寡核苷酸包含多种修饰,其中所述修饰包括选自以下的经修饰的糖部分:2’-O-甲氧基乙基修饰的糖部分、2’-甲氧基修饰的糖部分、2’-O-烷基修饰的糖部分、二环糖部分及其组合。
19.一种组合物,所述组合物包含权利要求10-18的任一项的一种或多种寡核苷酸和药学上可接受的赋形剂。
20.权利要求10-18的任一项的寡核苷酸在制备用于预防或治疗与至少一种三重四脯氨酸(TTP)多核苷酸和/或至少一种其编码产物有关的疾病的药物中的用途。
21.权利要求20的用途,其中与至少一种三重四脯氨酸(TTP)多核苷酸有关的疾病选自:关节炎、炎症、关节和皮肤炎症、炎症性肠病、克罗恩病、溃疡性结肠炎、癌症。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17581209P | 2009-05-06 | 2009-05-06 | |
US61/175812 | 2009-05-06 | ||
US61/175,812 | 2009-05-06 | ||
PCT/US2010/033836 WO2010129746A2 (en) | 2009-05-06 | 2010-05-06 | Treatment of tristetraproline (ttp) related diseases by inhibition of natural antisense transcript to ttp |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102803492A CN102803492A (zh) | 2012-11-28 |
CN102803492B true CN102803492B (zh) | 2016-06-29 |
Family
ID=43050868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201080027720.7A Active CN102803492B (zh) | 2009-05-06 | 2010-05-06 | 通过抑制针对三重四脯氨酸(ttp)的天然反义转录物来治疗ttp相关疾病 |
Country Status (8)
Country | Link |
---|---|
US (3) | US20120046236A1 (zh) |
EP (1) | EP2427552B1 (zh) |
JP (1) | JP6250930B2 (zh) |
KR (1) | KR101722541B1 (zh) |
CN (1) | CN102803492B (zh) |
CA (1) | CA2761142C (zh) |
ES (1) | ES2609655T3 (zh) |
WO (1) | WO2010129746A2 (zh) |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8906875B2 (en) | 2010-03-12 | 2014-12-09 | The Brigham And Women's Hospital, Inc. | Methods of treating vascular inflammatory disorders |
US9920317B2 (en) | 2010-11-12 | 2018-03-20 | The General Hospital Corporation | Polycomb-associated non-coding RNAs |
DK2638163T3 (en) | 2010-11-12 | 2017-07-24 | Massachusetts Gen Hospital | POLYCOMB-ASSOCIATED NON-CODING RNAs |
EP2663323B1 (en) | 2011-01-14 | 2017-08-16 | The General Hospital Corporation | Methods targeting mir-128 for regulating cholesterol/lipid metabolism |
US10184151B2 (en) | 2011-10-11 | 2019-01-22 | The Brigham And Women's Hospital, Inc. | Micrornas in neurodegenerative disorders |
JP2015518713A (ja) | 2012-05-16 | 2015-07-06 | ラナ セラピューティクス インコーポレイテッド | Utrn発現を調節するための組成物及び方法 |
EA201492116A1 (ru) | 2012-05-16 | 2015-05-29 | Рана Терапьютикс, Инк. | Композиции и способы для модулирования экспрессии mecp2 |
AU2013262699A1 (en) | 2012-05-16 | 2015-01-22 | Rana Therapeutics, Inc. | Compositions and methods for modulating ATP2A2 expression |
US10837014B2 (en) | 2012-05-16 | 2020-11-17 | Translate Bio Ma, Inc. | Compositions and methods for modulating SMN gene family expression |
CN104583399A (zh) | 2012-05-16 | 2015-04-29 | Rana医疗有限公司 | 用于调节血红蛋白基因家族表达的组合物和方法 |
AU2013262663A1 (en) | 2012-05-16 | 2015-01-22 | The General Hospital Corporation D/B/A Massachusetts General Hospital | Compositions and methods for modulating gene expression |
SG11201407483YA (en) | 2012-05-16 | 2014-12-30 | Rana Therapeutics Inc | Compositions and methods for modulating smn gene family expression |
WO2013184209A1 (en) | 2012-06-04 | 2013-12-12 | Ludwig Institute For Cancer Research Ltd. | Mif for use in methods of treating subjects with a neurodegenerative disorder |
EP3161159B1 (en) | 2014-06-25 | 2020-08-05 | The General Hospital Corporation | Targeting human satellite ii (hsatii) |
WO2016033472A1 (en) | 2014-08-29 | 2016-03-03 | Children's Medical Center Corporation | Methods and compositions for the treatment of cancer |
EP3212824A4 (en) | 2014-10-30 | 2018-08-08 | The General Hospital Corporation | Methods for modulating atrx-dependent gene repression |
EP3271460A4 (en) | 2015-03-17 | 2019-03-13 | The General Hospital Corporation | INTERACTOME RNA OF COMPLEX REPRESSIVE POLYCOMB 1 (PRC1) |
EP3283502A4 (en) | 2015-04-07 | 2019-04-03 | The General Hospital Corporation | METHODS FOR REACTIVATION OF GENES ON INACTIVE X CHROMOSOME |
CN108139375A (zh) | 2015-06-26 | 2018-06-08 | 贝斯以色列女执事医疗中心股份有限公司 | 靶向髓样衍生的抑制细胞中的四跨膜蛋白33(tspan33)的癌症疗法 |
WO2017066712A2 (en) | 2015-10-16 | 2017-04-20 | The Children's Medical Center Corporation | Modulators of telomere disease |
WO2017066796A2 (en) | 2015-10-16 | 2017-04-20 | The Children's Medical Center Corporation | Modulators of telomere disease |
US11001622B2 (en) | 2015-11-19 | 2021-05-11 | The Brigham And Women's Hospital, Inc. | Method of treating autoimmune disease with lymphocyte antigen CD5-like (CD5L) protein |
US11234996B2 (en) | 2016-02-25 | 2022-02-01 | The Brigham And Women's Hospital, Inc. | Treatment methods for fibrosis targeting SMOC2 |
CA3037046A1 (en) | 2016-10-31 | 2018-05-03 | University Of Massachusetts | Targeting microrna-101-3p in cancer therapy |
US11584932B2 (en) | 2016-11-01 | 2023-02-21 | The Research Foundation For The State University Of New York | 5-halouracil-modified microRNAs and their use in the treatment of cancer |
EP3612232A1 (en) | 2017-04-21 | 2020-02-26 | The Broad Institute, Inc. | Targeted delivery to beta cells |
WO2019036375A1 (en) | 2017-08-14 | 2019-02-21 | Sanford Burnham Prebys Medical Discovery Institute | CARDIOGENIC MESODERMA TRAINING REGULATORS |
EP3703669A4 (en) | 2017-11-01 | 2021-11-10 | Dana-Farber Cancer Institute, Inc. | Methods of treating cancers |
WO2020047229A1 (en) | 2018-08-29 | 2020-03-05 | University Of Massachusetts | Inhibition of protein kinases to treat friedreich ataxia |
WO2020171889A1 (en) | 2019-02-19 | 2020-08-27 | University Of Rochester | Blocking lipid accumulation or inflammation in thyroid eye disease |
KR102443953B1 (ko) * | 2020-04-13 | 2022-09-15 | 동아대학교 산학협력단 | 항암제 내성 암 치료용 항암 보조제, 약학 조성물 및 이를 포함하는 키트 |
EP4467983A1 (en) * | 2023-05-26 | 2024-11-27 | King Faisal Specialist Hospital & Research Centre | Molecular identification of compounds targeting tristetraprolin (ttp) and ttp phosphorylation |
CN117721152B (zh) * | 2023-12-29 | 2024-08-30 | 广州市第一人民医院(广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院) | Ttp在制备骨关节炎药物中的应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004044202A1 (en) * | 2002-11-14 | 2004-05-27 | Toolgen, Inc. | Method for the gene regulation at both transcription and post-transcription levels |
CN1602427A (zh) * | 2001-12-12 | 2005-03-30 | 默克专利股份公司 | 三重四脯氨酸碱性蛋白用于保护心脏避免发生心脏损伤的抑制作用 |
CN1798579A (zh) * | 2003-04-01 | 2006-07-05 | 因特拉迪格姆公司 | 肿瘤生长抑制的目标 |
WO2007087113A2 (en) * | 2005-12-28 | 2007-08-02 | The Scripps Research Institute | Natural antisense and non-coding rna transcripts as drug targets |
US20070248590A1 (en) * | 2005-12-02 | 2007-10-25 | Sirtris Pharmaceuticals, Inc. | Modulators of CDC2-like kinases (CLKS) and methods of use thereof |
Family Cites Families (389)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US558548A (en) | 1896-04-21 | Picture hanging device | ||
US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
US4426330A (en) | 1981-07-20 | 1984-01-17 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US4534899A (en) | 1981-07-20 | 1985-08-13 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US5023243A (en) | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
US4476301A (en) | 1982-04-29 | 1984-10-09 | Centre National De La Recherche Scientifique | Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon |
JPS5927900A (ja) | 1982-08-09 | 1984-02-14 | Wakunaga Seiyaku Kk | 固定化オリゴヌクレオチド |
FR2540122B1 (fr) | 1983-01-27 | 1985-11-29 | Centre Nat Rech Scient | Nouveaux composes comportant une sequence d'oligonucleotide liee a un agent d'intercalation, leur procede de synthese et leur application |
US4605735A (en) | 1983-02-14 | 1986-08-12 | Wakunaga Seiyaku Kabushiki Kaisha | Oligonucleotide derivatives |
US4948882A (en) | 1983-02-22 | 1990-08-14 | Syngene, Inc. | Single-stranded labelled oligonucleotides, reactive monomers and methods of synthesis |
NZ207394A (en) | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
US4824941A (en) | 1983-03-10 | 1989-04-25 | Julian Gordon | Specific antibody to the native form of 2'5'-oligonucleotides, the method of preparation and the use as reagents in immunoassays or for binding 2'5'-oligonucleotides in biological systems |
US4587044A (en) | 1983-09-01 | 1986-05-06 | The Johns Hopkins University | Linkage of proteins to nucleic acids |
US5118800A (en) | 1983-12-20 | 1992-06-02 | California Institute Of Technology | Oligonucleotides possessing a primary amino group in the terminal nucleotide |
US5118802A (en) | 1983-12-20 | 1992-06-02 | California Institute Of Technology | DNA-reporter conjugates linked via the 2' or 5'-primary amino group of the 5'-terminal nucleoside |
US5550111A (en) | 1984-07-11 | 1996-08-27 | Temple University-Of The Commonwealth System Of Higher Education | Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof |
FR2567892B1 (fr) | 1984-07-19 | 1989-02-17 | Centre Nat Rech Scient | Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons |
US5258506A (en) | 1984-10-16 | 1993-11-02 | Chiron Corporation | Photolabile reagents for incorporation into oligonucleotide chains |
US5367066A (en) | 1984-10-16 | 1994-11-22 | Chiron Corporation | Oligonucleotides with selectably cleavable and/or abasic sites |
US5430136A (en) | 1984-10-16 | 1995-07-04 | Chiron Corporation | Oligonucleotides having selectably cleavable and/or abasic sites |
US4828979A (en) | 1984-11-08 | 1989-05-09 | Life Technologies, Inc. | Nucleotide analogs for nucleic acid labeling and detection |
US4754065A (en) | 1984-12-18 | 1988-06-28 | Cetus Corporation | Precursor to nucleic acid probe |
FR2575751B1 (fr) | 1985-01-08 | 1987-04-03 | Pasteur Institut | Nouveaux nucleosides de derives de l'adenosine, leur preparation et leurs applications biologiques |
US5235033A (en) | 1985-03-15 | 1993-08-10 | Anti-Gene Development Group | Alpha-morpholino ribonucleoside derivatives and polymers thereof |
US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
US5166315A (en) | 1989-12-20 | 1992-11-24 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
US5405938A (en) | 1989-12-20 | 1995-04-11 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
US5506337A (en) | 1985-03-15 | 1996-04-09 | Antivirals Inc. | Morpholino-subunit combinatorial library and method |
US5034506A (en) | 1985-03-15 | 1991-07-23 | Anti-Gene Development Group | Uncharged morpholino-based polymers having achiral intersubunit linkages |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US4762779A (en) | 1985-06-13 | 1988-08-09 | Amgen Inc. | Compositions and methods for functionalizing nucleic acids |
US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
US5317098A (en) | 1986-03-17 | 1994-05-31 | Hiroaki Shizuya | Non-radioisotope tagging of fragments |
JPS638396A (ja) | 1986-06-30 | 1988-01-14 | Wakunaga Pharmaceut Co Ltd | ポリ標識化オリゴヌクレオチド誘導体 |
DE3788914T2 (de) | 1986-09-08 | 1994-08-25 | Ajinomoto Kk | Verbindungen zur Spaltung von RNS an eine spezifische Position, Oligomere, verwendet bei der Herstellung dieser Verbindungen und Ausgangsprodukte für die Synthese dieser Oligomere. |
US5276019A (en) | 1987-03-25 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US5264423A (en) | 1987-03-25 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US4904582A (en) | 1987-06-11 | 1990-02-27 | Synthetic Genetics | Novel amphiphilic nucleic acid conjugates |
CA1340032C (en) | 1987-06-24 | 1998-09-08 | Jim Haralambidis | Lucleoside derivatives |
US5585481A (en) | 1987-09-21 | 1996-12-17 | Gen-Probe Incorporated | Linking reagents for nucleotide probes |
US4924624A (en) | 1987-10-22 | 1990-05-15 | Temple University-Of The Commonwealth System Of Higher Education | 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof |
US5188897A (en) | 1987-10-22 | 1993-02-23 | Temple University Of The Commonwealth System Of Higher Education | Encapsulated 2',5'-phosphorothioate oligoadenylates |
US5525465A (en) | 1987-10-28 | 1996-06-11 | Howard Florey Institute Of Experimental Physiology And Medicine | Oligonucleotide-polyamide conjugates and methods of production and applications of the same |
DE3738460A1 (de) | 1987-11-12 | 1989-05-24 | Max Planck Gesellschaft | Modifizierte oligonukleotide |
US4866042A (en) | 1987-11-18 | 1989-09-12 | Neuwelt Edward A | Method for the delivery of genetic material across the blood brain barrier |
US5403711A (en) | 1987-11-30 | 1995-04-04 | University Of Iowa Research Foundation | Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled nucleic acid probe is cleaved |
EP0348458B1 (en) | 1987-11-30 | 1997-04-09 | University Of Iowa Research Foundation | Dna molecules stabilized by modifications of the 3'-terminal phosphodiester linkage and their use as nucleic acid probes and as therapeutic agents to block the expression of specifically targeted genes |
US5288512A (en) | 1987-12-15 | 1994-02-22 | The Procter & Gamble Company | Reduced calorie fats made from triglycerides containing medium and long chain fatty acids |
US5082830A (en) | 1988-02-26 | 1992-01-21 | Enzo Biochem, Inc. | End labeled nucleotide probe |
NL8800756A (nl) | 1988-03-25 | 1989-10-16 | Vereniging Voor Christelijk Wetenschappelijk Onderwijs | Genetisch gemanipuleerde plantecellen en planten, alsmede daarvoor bruikbaar recombinant dna. |
WO1989009221A1 (en) | 1988-03-25 | 1989-10-05 | University Of Virginia Alumni Patents Foundation | Oligonucleotide n-alkylphosphoramidates |
US5278302A (en) | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
US5109124A (en) | 1988-06-01 | 1992-04-28 | Biogen, Inc. | Nucleic acid probe linked to a label having a terminal cysteine |
US5216141A (en) | 1988-06-06 | 1993-06-01 | Benner Steven A | Oligonucleotide analogs containing sulfur linkages |
US5175273A (en) | 1988-07-01 | 1992-12-29 | Genentech, Inc. | Nucleic acid intercalating agents |
US5262536A (en) | 1988-09-15 | 1993-11-16 | E. I. Du Pont De Nemours And Company | Reagents for the preparation of 5'-tagged oligonucleotides |
US5512439A (en) | 1988-11-21 | 1996-04-30 | Dynal As | Oligonucleotide-linked magnetic particles and uses thereof |
US5599923A (en) | 1989-03-06 | 1997-02-04 | Board Of Regents, University Of Tx | Texaphyrin metal complexes having improved functionalization |
US5457183A (en) | 1989-03-06 | 1995-10-10 | Board Of Regents, The University Of Texas System | Hydroxylated texaphyrins |
US5354844A (en) | 1989-03-16 | 1994-10-11 | Boehringer Ingelheim International Gmbh | Protein-polycation conjugates |
US6294520B1 (en) | 1989-03-27 | 2001-09-25 | Albert T. Naito | Material for passage through the blood-brain barrier |
US5108921A (en) | 1989-04-03 | 1992-04-28 | Purdue Research Foundation | Method for enhanced transmembrane transport of exogenous molecules |
US5391723A (en) | 1989-05-31 | 1995-02-21 | Neorx Corporation | Oligonucleotide conjugates |
US5256775A (en) | 1989-06-05 | 1993-10-26 | Gilead Sciences, Inc. | Exonuclease-resistant oligonucleotides |
US4958013A (en) | 1989-06-06 | 1990-09-18 | Northwestern University | Cholesteryl modified oligonucleotides |
US5227170A (en) | 1989-06-22 | 1993-07-13 | Vestar, Inc. | Encapsulation process |
US6203976B1 (en) | 1989-07-18 | 2001-03-20 | Osi Pharmaceuticals, Inc. | Methods of preparing compositions comprising chemicals capable of transcriptional modulation |
US5451463A (en) | 1989-08-28 | 1995-09-19 | Clontech Laboratories, Inc. | Non-nucleoside 1,3-diol reagents for labeling synthetic oligonucleotides |
US5134066A (en) | 1989-08-29 | 1992-07-28 | Monsanto Company | Improved probes using nucleosides containing 3-dezauracil analogs |
US5254469A (en) | 1989-09-12 | 1993-10-19 | Eastman Kodak Company | Oligonucleotide-enzyme conjugate that can be used as a probe in hybridization assays and polymerase chain reaction procedures |
US5591722A (en) | 1989-09-15 | 1997-01-07 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides and their antiviral activity |
US5356633A (en) | 1989-10-20 | 1994-10-18 | Liposome Technology, Inc. | Method of treatment of inflamed tissues |
US5013556A (en) | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5527528A (en) | 1989-10-20 | 1996-06-18 | Sequus Pharmaceuticals, Inc. | Solid-tumor treatment method |
US5399676A (en) | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
US5264562A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences, Inc. | Oligonucleotide analogs with novel linkages |
JPH05504552A (ja) | 1989-10-24 | 1993-07-15 | ギリアド サイエンシズ,インコーポレイテッド | 2’位が改変されたオリゴヌクレオチド |
US5264564A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences | Oligonucleotide analogs with novel linkages |
US5292873A (en) | 1989-11-29 | 1994-03-08 | The Research Foundation Of State University Of New York | Nucleic acids labeled with naphthoquinone probe |
US5177198A (en) | 1989-11-30 | 1993-01-05 | University Of N.C. At Chapel Hill | Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates |
US5457189A (en) | 1989-12-04 | 1995-10-10 | Isis Pharmaceuticals | Antisense oligonucleotide inhibition of papillomavirus |
US5130302A (en) | 1989-12-20 | 1992-07-14 | Boron Bilogicals, Inc. | Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same |
US5469854A (en) | 1989-12-22 | 1995-11-28 | Imarx Pharmaceutical Corp. | Methods of preparing gas-filled liposomes |
US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
US5486603A (en) | 1990-01-08 | 1996-01-23 | Gilead Sciences, Inc. | Oligonucleotide having enhanced binding affinity |
US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5459255A (en) | 1990-01-11 | 1995-10-17 | Isis Pharmaceuticals, Inc. | N-2 substituted purines |
US5852188A (en) | 1990-01-11 | 1998-12-22 | Isis Pharmaceuticals, Inc. | Oligonucleotides having chiral phosphorus linkages |
US5670633A (en) | 1990-01-11 | 1997-09-23 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides that detect and modulate gene expression |
US5646265A (en) | 1990-01-11 | 1997-07-08 | Isis Pharmceuticals, Inc. | Process for the preparation of 2'-O-alkyl purine phosphoramidites |
US5578718A (en) | 1990-01-11 | 1996-11-26 | Isis Pharmaceuticals, Inc. | Thiol-derivatized nucleosides |
US5681941A (en) | 1990-01-11 | 1997-10-28 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
US5587470A (en) | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
US5623065A (en) | 1990-08-13 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Gapped 2' modified oligonucleotides |
US5149797A (en) | 1990-02-15 | 1992-09-22 | The Worcester Foundation For Experimental Biology | Method of site-specific alteration of rna and production of encoded polypeptides |
US5220007A (en) | 1990-02-15 | 1993-06-15 | The Worcester Foundation For Experimental Biology | Method of site-specific alteration of RNA and production of encoded polypeptides |
US5214136A (en) | 1990-02-20 | 1993-05-25 | Gilead Sciences, Inc. | Anthraquinone-derivatives oligonucleotides |
WO1991013080A1 (en) | 1990-02-20 | 1991-09-05 | Gilead Sciences, Inc. | Pseudonucleosides and pseudonucleotides and their polymers |
US5321131A (en) | 1990-03-08 | 1994-06-14 | Hybridon, Inc. | Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling |
US5470967A (en) | 1990-04-10 | 1995-11-28 | The Dupont Merck Pharmaceutical Company | Oligonucleotide analogs with sulfamate linkages |
US5264618A (en) | 1990-04-19 | 1993-11-23 | Vical, Inc. | Cationic lipids for intracellular delivery of biologically active molecules |
GB9009980D0 (en) | 1990-05-03 | 1990-06-27 | Amersham Int Plc | Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides |
US6034233A (en) | 1990-05-04 | 2000-03-07 | Isis Pharmaceuticals Inc. | 2'-O-alkylated oligoribonucleotides and phosphorothioate analogs complementary to portions of the HIV genome |
DK0455905T3 (da) | 1990-05-11 | 1998-12-07 | Microprobe Corp | Dipsticks til nukleinsyrehybridiseringsassays og fremgangsmåde til kovalent immobilisering af oligonukleotider |
IE66205B1 (en) | 1990-06-14 | 1995-12-13 | Paul A Bartlett | Polypeptide analogs |
US5650489A (en) | 1990-07-02 | 1997-07-22 | The Arizona Board Of Regents | Random bio-oligomer library, a method of synthesis thereof, and a method of use thereof |
US5688941A (en) | 1990-07-27 | 1997-11-18 | Isis Pharmaceuticals, Inc. | Methods of making conjugated 4' desmethyl nucleoside analog compounds |
US5608046A (en) | 1990-07-27 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Conjugated 4'-desmethyl nucleoside analog compounds |
US5677437A (en) | 1990-07-27 | 1997-10-14 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
US5541307A (en) | 1990-07-27 | 1996-07-30 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs and solid phase synthesis thereof |
US5218105A (en) | 1990-07-27 | 1993-06-08 | Isis Pharmaceuticals | Polyamine conjugated oligonucleotides |
US5610289A (en) | 1990-07-27 | 1997-03-11 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogues |
US5602240A (en) | 1990-07-27 | 1997-02-11 | Ciba Geigy Ag. | Backbone modified oligonucleotide analogs |
US5138045A (en) | 1990-07-27 | 1992-08-11 | Isis Pharmaceuticals | Polyamine conjugated oligonucleotides |
US5618704A (en) | 1990-07-27 | 1997-04-08 | Isis Pharmacueticals, Inc. | Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling |
US5614617A (en) | 1990-07-27 | 1997-03-25 | Isis Pharmaceuticals, Inc. | Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression |
US5489677A (en) | 1990-07-27 | 1996-02-06 | Isis Pharmaceuticals, Inc. | Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms |
US5623070A (en) | 1990-07-27 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
BR9106729A (pt) | 1990-08-03 | 1993-07-20 | Sterling Winthrop Inc | Composto,processos para inibir a degradacao por nuclease de compostos e para estabilizar sequencias de nicleotideos ou oligonucleosideos,composicao utilizavel para inibir expressao de genes e processo para inibir expressao de genes em um mamifero necessitando de tal tratamento |
US5245022A (en) | 1990-08-03 | 1993-09-14 | Sterling Drug, Inc. | Exonuclease resistant terminally substituted oligonucleotides |
US5177196A (en) | 1990-08-16 | 1993-01-05 | Microprobe Corporation | Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof |
US5512667A (en) | 1990-08-28 | 1996-04-30 | Reed; Michael W. | Trifunctional intermediates for preparing 3'-tailed oligonucleotides |
US5214134A (en) | 1990-09-12 | 1993-05-25 | Sterling Winthrop Inc. | Process of linking nucleosides with a siloxane bridge |
US5561225A (en) | 1990-09-19 | 1996-10-01 | Southern Research Institute | Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages |
US5596086A (en) | 1990-09-20 | 1997-01-21 | Gilead Sciences, Inc. | Modified internucleoside linkages having one nitrogen and two carbon atoms |
US5432272A (en) | 1990-10-09 | 1995-07-11 | Benner; Steven A. | Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases |
CA2095212A1 (en) | 1990-11-08 | 1992-05-09 | Sudhir Agrawal | Incorporation of multiple reporter groups on synthetic oligonucleotides |
CA2096222C (en) | 1990-11-13 | 1998-12-29 | Stephen D. Lupton | Bifunctional selectable fusion genes |
JP3220180B2 (ja) | 1991-05-23 | 2001-10-22 | 三菱化学株式会社 | 薬剤含有タンパク質結合リポソーム |
US5714331A (en) | 1991-05-24 | 1998-02-03 | Buchardt, Deceased; Ole | Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility |
US5719262A (en) | 1993-11-22 | 1998-02-17 | Buchardt, Deceased; Ole | Peptide nucleic acids having amino acid side chains |
US5539082A (en) | 1993-04-26 | 1996-07-23 | Nielsen; Peter E. | Peptide nucleic acids |
US5371241A (en) | 1991-07-19 | 1994-12-06 | Pharmacia P-L Biochemicals Inc. | Fluorescein labelled phosphoramidites |
US6307040B1 (en) | 1992-03-05 | 2001-10-23 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides that detect and modulate gene expression |
US5571799A (en) | 1991-08-12 | 1996-11-05 | Basco, Ltd. | (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response |
US5474796A (en) | 1991-09-04 | 1995-12-12 | Protogene Laboratories, Inc. | Method and apparatus for conducting an array of chemical reactions on a support surface |
NZ244306A (en) | 1991-09-30 | 1995-07-26 | Boehringer Ingelheim Int | Composition for introducing nucleic acid complexes into eucaryotic cells, complex containing nucleic acid and endosomolytic agent, peptide with endosomolytic domain and nucleic acid binding domain and preparation |
US5521291A (en) | 1991-09-30 | 1996-05-28 | Boehringer Ingelheim International, Gmbh | Conjugates for introducing nucleic acid into higher eucaryotic cells |
US5661134A (en) | 1991-10-15 | 1997-08-26 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating Ha-ras or Ki-ras having phosphorothioate linkages of high chiral purity |
US5576302A (en) | 1991-10-15 | 1996-11-19 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity |
DE59208572D1 (de) | 1991-10-17 | 1997-07-10 | Ciba Geigy Ag | Bicyclische Nukleoside, Oligonukleotide, Verfahren zu deren Herstellung und Zwischenprodukte |
US6335434B1 (en) | 1998-06-16 | 2002-01-01 | Isis Pharmaceuticals, Inc., | Nucleosidic and non-nucleosidic folate conjugates |
US5605662A (en) | 1993-11-01 | 1997-02-25 | Nanogen, Inc. | Active programmable electronic devices for molecular biological analysis and diagnostics |
US5484908A (en) | 1991-11-26 | 1996-01-16 | Gilead Sciences, Inc. | Oligonucleotides containing 5-propynyl pyrimidines |
US5359044A (en) | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
US5700922A (en) | 1991-12-24 | 1997-12-23 | Isis Pharmaceuticals, Inc. | PNA-DNA-PNA chimeric macromolecules |
US5595726A (en) | 1992-01-21 | 1997-01-21 | Pharmacyclics, Inc. | Chromophore probe for detection of nucleic acid |
US5565552A (en) | 1992-01-21 | 1996-10-15 | Pharmacyclics, Inc. | Method of expanded porphyrin-oligonucleotide conjugate synthesis |
FR2687679B1 (fr) | 1992-02-05 | 1994-10-28 | Centre Nat Rech Scient | Oligothionucleotides. |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
US5633360A (en) | 1992-04-14 | 1997-05-27 | Gilead Sciences, Inc. | Oligonucleotide analogs capable of passive cell membrane permeation |
IL101600A (en) | 1992-04-15 | 2000-02-29 | Yissum Res Dev Co | Synthetic partially phosphorothioated antisense oligodeoxynucleotides and pharmaceutical compositions containing them |
US5434257A (en) | 1992-06-01 | 1995-07-18 | Gilead Sciences, Inc. | Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages |
EP0577558A2 (de) | 1992-07-01 | 1994-01-05 | Ciba-Geigy Ag | Carbocyclische Nukleoside mit bicyclischen Ringen, Oligonukleotide daraus, Verfahren zu deren Herstellung, deren Verwendung und Zwischenproduckte |
US5272250A (en) | 1992-07-10 | 1993-12-21 | Spielvogel Bernard F | Boronated phosphoramidate compounds |
US5652355A (en) | 1992-07-23 | 1997-07-29 | Worcester Foundation For Experimental Biology | Hybrid oligonucleotide phosphorothioates |
US5288514A (en) | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
JPH08501686A (ja) | 1992-09-25 | 1996-02-27 | ローン−プーラン・ロレ・ソシエテ・アノニム | 中枢神経系、特に脳における細胞への外来遺伝子の転移のためのアデノウィルスベクター |
US6710174B2 (en) | 2001-09-13 | 2004-03-23 | Isis Pharmaceuticals, Inc. | Antisense inhibition of vascular endothelial growth factor receptor-1 expression |
WO1994009148A1 (en) | 1992-10-15 | 1994-04-28 | Toray Industries, Inc. | Process for producing major histocompatibility antigen class ii protein and material having the same immobilized thereon |
US5583020A (en) | 1992-11-24 | 1996-12-10 | Ribozyme Pharmaceuticals, Inc. | Permeability enhancers for negatively charged polynucleotides |
US5574142A (en) | 1992-12-15 | 1996-11-12 | Microprobe Corporation | Peptide linkers for improved oligonucleotide delivery |
JP3351476B2 (ja) | 1993-01-22 | 2002-11-25 | 三菱化学株式会社 | リン脂質誘導体及びそれを含有するリポソーム |
US5476925A (en) | 1993-02-01 | 1995-12-19 | Northwestern University | Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups |
US5395619A (en) | 1993-03-03 | 1995-03-07 | Liposome Technology, Inc. | Lipid-polymer conjugates and liposomes |
GB9304618D0 (en) | 1993-03-06 | 1993-04-21 | Ciba Geigy Ag | Chemical compounds |
AU6449394A (en) | 1993-03-30 | 1994-10-24 | Sterling Winthrop Inc. | Acyclic nucleoside analogs and oligonucleotide sequences containing them |
HU9501974D0 (en) | 1993-03-31 | 1995-09-28 | Sterling Winthrop Inc | Oligonucleotides with amide linkages replacing phosphodiester linkages |
DE4311944A1 (de) | 1993-04-10 | 1994-10-13 | Degussa | Umhüllte Natriumpercarbonatpartikel, Verfahren zu deren Herstellung und sie enthaltende Wasch-, Reinigungs- und Bleichmittelzusammensetzungen |
US5462854A (en) | 1993-04-19 | 1995-10-31 | Beckman Instruments, Inc. | Inverse linkage oligonucleotides for chemical and enzymatic processes |
DE69435005T2 (de) | 1993-05-11 | 2008-04-17 | The University Of North Carolina At Chapel Hill | Antisense Oligonukleotide die anomales Splicing verhindern und deren Verwendung |
AU6953394A (en) | 1993-05-21 | 1994-12-20 | Targeted Genetics Corporation | Bifunctional selectable fusion genes based on the cytosine deaminase (cd) gene |
US5534259A (en) | 1993-07-08 | 1996-07-09 | Liposome Technology, Inc. | Polymer compound and coated particle composition |
US5417978A (en) | 1993-07-29 | 1995-05-23 | Board Of Regents, The University Of Texas System | Liposomal antisense methyl phosphonate oligonucleotides and methods for their preparation and use |
JP3484197B2 (ja) | 1993-09-03 | 2004-01-06 | アイシス・ファーマシューティカルス・インコーポレーテッド | アミン誘導化ヌクレオシドおよびオリゴヌクレオシド |
US5491084A (en) | 1993-09-10 | 1996-02-13 | The Trustees Of Columbia University In The City Of New York | Uses of green-fluorescent protein |
US5502177A (en) | 1993-09-17 | 1996-03-26 | Gilead Sciences, Inc. | Pyrimidine derivatives for labeled binding partners |
EP0889122A3 (en) | 1993-11-30 | 1999-03-03 | McGILL UNIVERSITY | Inhibition of DNA Methyltransferase |
US5908779A (en) | 1993-12-01 | 1999-06-01 | University Of Connecticut | Targeted RNA degradation using nuclear antisense RNA |
US5457187A (en) | 1993-12-08 | 1995-10-10 | Board Of Regents University Of Nebraska | Oligonucleotides containing 5-fluorouracil |
NZ278490A (en) | 1993-12-09 | 1998-03-25 | Univ Jefferson | Chimeric polynucleotide with both ribo- and deoxyribonucleotides in one strand and deoxyribonucleotides in a second strand |
US5446137B1 (en) | 1993-12-09 | 1998-10-06 | Behringwerke Ag | Oligonucleotides containing 4'-substituted nucleotides |
US5595756A (en) | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
US5519134A (en) | 1994-01-11 | 1996-05-21 | Isis Pharmaceuticals, Inc. | Pyrrolidine-containing monomers and oligomers |
US5593853A (en) | 1994-02-09 | 1997-01-14 | Martek Corporation | Generation and screening of synthetic drug libraries |
EP0745134A1 (en) | 1994-02-22 | 1996-12-04 | Danafarber Cancer Institute | Nucleic acid delivery system, method of synthesis and uses thereof |
US5539083A (en) | 1994-02-23 | 1996-07-23 | Isis Pharmaceuticals, Inc. | Peptide nucleic acid combinatorial libraries and improved methods of synthesis |
US5902880A (en) | 1994-08-19 | 1999-05-11 | Ribozyme Pharmaceuticals, Inc. | RNA polymerase III-based expression of therapeutic RNAs |
US6551618B2 (en) | 1994-03-15 | 2003-04-22 | University Of Birmingham | Compositions and methods for delivery of agents for neuronal regeneration and survival |
US6015880A (en) | 1994-03-16 | 2000-01-18 | California Institute Of Technology | Method and substrate for performing multiple sequential reactions on a matrix |
US5596091A (en) | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
US5627053A (en) | 1994-03-29 | 1997-05-06 | Ribozyme Pharmaceuticals, Inc. | 2'deoxy-2'-alkylnucleotide containing nucleic acid |
US5625050A (en) | 1994-03-31 | 1997-04-29 | Amgen Inc. | Modified oligonucleotides and intermediates useful in nucleic acid therapeutics |
US5525711A (en) | 1994-05-18 | 1996-06-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pteridine nucleotide analogs as fluorescent DNA probes |
US5807522A (en) | 1994-06-17 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for fabricating microarrays of biological samples |
US5543152A (en) | 1994-06-20 | 1996-08-06 | Inex Pharmaceuticals Corporation | Sphingosomes for enhanced drug delivery |
US5525735A (en) | 1994-06-22 | 1996-06-11 | Affymax Technologies Nv | Methods for synthesizing diverse collections of pyrrolidine compounds |
US5549974A (en) | 1994-06-23 | 1996-08-27 | Affymax Technologies Nv | Methods for the solid phase synthesis of thiazolidinones, metathiazanones, and derivatives thereof |
US5597696A (en) | 1994-07-18 | 1997-01-28 | Becton Dickinson And Company | Covalent cyanine dye oligonucleotide conjugates |
US5597909A (en) | 1994-08-25 | 1997-01-28 | Chiron Corporation | Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use |
US5580731A (en) | 1994-08-25 | 1996-12-03 | Chiron Corporation | N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith |
US5591721A (en) | 1994-10-25 | 1997-01-07 | Hybridon, Inc. | Method of down-regulating gene expression |
US6645943B1 (en) | 1994-10-25 | 2003-11-11 | Hybridon, Inc. | Method of down-regulating gene expression |
US5512295A (en) | 1994-11-10 | 1996-04-30 | The Board Of Trustees Of The Leland Stanford Junior University | Synthetic liposomes for enhanced uptake and delivery |
FR2727867B1 (fr) | 1994-12-13 | 1997-01-31 | Rhone Poulenc Rorer Sa | Transfert de genes dans les motoneurones medullaires au moyen de vecteurs adenoviraux |
GB9501465D0 (en) | 1995-01-25 | 1995-03-15 | King S College London | Nucleoside phosphorothioate derivatives,synthesis and use thereof |
DE19502912A1 (de) | 1995-01-31 | 1996-08-01 | Hoechst Ag | G-Cap Stabilisierte Oligonucleotide |
IT1276642B1 (it) | 1995-03-03 | 1997-11-03 | Consiglio Nazionale Ricerche | Trascritto antisenso presente in linfociti b ed oligodeossinucleotidi sintetici utili per inibirne l'azione |
IT1275862B1 (it) | 1995-03-03 | 1997-10-24 | Consiglio Nazionale Ricerche | Trascritto antisenso associato ad alcuni tipi di cellule tumorali ed oligodeossinucleotidi sintetici utili nella diagnosi e nel trattamento |
US5543165A (en) | 1995-06-06 | 1996-08-06 | Hill; Julie B. | Process of making a soluble tea product with champagne-like properties |
US5739311A (en) | 1995-06-07 | 1998-04-14 | Gen-Probe Incorporated | Enzymatic synthesis of phosphorothioate oligonucleotides using restriction endonucleases |
US5569588A (en) | 1995-08-09 | 1996-10-29 | The Regents Of The University Of California | Methods for drug screening |
US5652356A (en) | 1995-08-17 | 1997-07-29 | Hybridon, Inc. | Inverted chimeric and hybrid oligonucleotides |
KR19990082476A (ko) | 1996-02-14 | 1999-11-25 | 하우스 한스 루돌프, 긴터 베아트리체 | 당-변형되어 갭이 형성된 올리고뉴클레오티드 |
EP0888385B1 (en) | 1996-03-14 | 2003-08-20 | Genentech, Inc. | Gdnf receptor and uses thereof |
AU2733697A (en) | 1996-04-17 | 1997-11-07 | Aronex Pharmaceuticals, Inc. | Antisense inhibitors of vascular endothelial growth factor (vegf/vpf) expression |
US5786213A (en) | 1996-04-18 | 1998-07-28 | Board Of Regents, The University Of Texas System | Inhibition of endogenous gastrin expression for treatment of colorectal cancer |
WO1997042820A1 (en) * | 1996-05-16 | 1997-11-20 | Duke University | Tristetraprolin |
US5756710A (en) | 1996-06-05 | 1998-05-26 | The Trustees Of Columbia University In City Of New York | Phosphorothioate oligonucleotides that bind to the V3-loop and uses thereof |
US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US5849902A (en) | 1996-09-26 | 1998-12-15 | Oligos Etc. Inc. | Three component chimeric antisense oligonucleotides |
US5739119A (en) | 1996-11-15 | 1998-04-14 | Galli; Rachel L. | Antisense oligonucleotides specific for the muscarinic type 2 acetylcholine receptor MRNA |
US7008776B1 (en) | 1996-12-06 | 2006-03-07 | Aventis Pharmaceuticals Inc. | Compositions and methods for effecting the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein AI very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol |
US7235653B2 (en) | 1996-12-31 | 2007-06-26 | Isis Pharmaceuticals, Inc. | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
JP3756313B2 (ja) | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
US6489455B2 (en) * | 1997-05-21 | 2002-12-03 | Clontech Laboratories, Inc. | Methods of assaying differential expression |
US6013786A (en) | 1997-08-22 | 2000-01-11 | Hybridon, Inc. | MDM2-specific antisense oligonucleotides |
US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
US7572582B2 (en) | 1997-09-12 | 2009-08-11 | Exiqon A/S | Oligonucleotide analogues |
CN1273476C (zh) | 1997-09-12 | 2006-09-06 | 埃克西康有限公司 | 寡核苷酸类似物 |
US7285288B1 (en) | 1997-10-03 | 2007-10-23 | Board Of Regents, The University Of Texas System | Inhibition of Bcl-2 protein expression by liposomal antisense oligodeoxynucleotides |
US6034883A (en) | 1998-01-29 | 2000-03-07 | Tinney; Charles E. | Solid state director for beams |
US6175409B1 (en) | 1999-04-02 | 2001-01-16 | Symyx Technologies, Inc. | Flow-injection analysis and variable-flow light-scattering methods and apparatus for characterizing polymers |
US7321828B2 (en) | 1998-04-13 | 2008-01-22 | Isis Pharmaceuticals, Inc. | System of components for preparing oligonucleotides |
US20040186071A1 (en) | 1998-04-13 | 2004-09-23 | Bennett C. Frank | Antisense modulation of CD40 expression |
US6221587B1 (en) | 1998-05-12 | 2001-04-24 | Isis Pharmceuticals, Inc. | Identification of molecular interaction sites in RNA for novel drug discovery |
US6833361B2 (en) | 1998-05-26 | 2004-12-21 | Ribapharm, Inc. | Nucleosides having bicyclic sugar moiety |
HUP0102152A3 (en) | 1998-05-26 | 2002-04-29 | Icn Pharmaceuticals Inc Costa | Nucleosid and oligo nucleotid analogues having bicyclic sugar derivative |
US20030139359A1 (en) | 2001-12-04 | 2003-07-24 | Isis Pharmaceuticals Inc. | Antisense modulation of phospholipid scramblase 3 expression |
US6100090A (en) | 1999-06-25 | 2000-08-08 | Isis Pharmaceuticals Inc. | Antisense inhibition of PI3K p85 expression |
US6242589B1 (en) | 1998-07-14 | 2001-06-05 | Isis Pharmaceuticals, Inc. | Phosphorothioate oligonucleotides having modified internucleoside linkages |
US6867294B1 (en) | 1998-07-14 | 2005-03-15 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
US6214986B1 (en) | 1998-10-07 | 2001-04-10 | Isis Pharmaceuticals, Inc. | Antisense modulation of bcl-x expression |
US6376541B1 (en) | 1998-11-06 | 2002-04-23 | Alcon Manufacturing, Ltd. | Upregulation of endogenous prostaglandins to lower intraocular pressure |
US5985663A (en) | 1998-11-25 | 1999-11-16 | Isis Pharmaceuticals Inc. | Antisense inhibition of interleukin-15 expression |
AU776512B2 (en) | 1999-01-27 | 2004-09-09 | David Laurence Becker | Formulations comprising antisense nucleotides to connexins |
AU758956B2 (en) | 1999-02-12 | 2003-04-03 | Daiichi Sankyo Company, Limited | Novel nucleosides and oligonucleotide analogues |
EP1163254B1 (en) | 1999-02-26 | 2008-01-30 | The University of British Columbia | Trpm-2 antisense therapy |
US20040137423A1 (en) | 1999-03-15 | 2004-07-15 | Hayden Michael R. | Compositions and methods for modulating HDL cholesterol and triglyceride levels |
ATE364696T1 (de) | 1999-03-15 | 2007-07-15 | Univ British Columbia | Abc1 polypeptide und verfahren und reagenzien zur modulation des cholesterolgehalts |
US7084125B2 (en) | 1999-03-18 | 2006-08-01 | Exiqon A/S | Xylo-LNA analogues |
KR20020007331A (ko) | 1999-03-18 | 2002-01-26 | 추후제출 | 특이 lna 프라이머에 의한 유전자중의 돌연변이 검출 |
US6734291B2 (en) | 1999-03-24 | 2004-05-11 | Exiqon A/S | Synthesis of [2.2.1]bicyclo nucleosides |
JP4768132B2 (ja) | 1999-03-24 | 2011-09-07 | エクシコン エ/エス | [2.2.1]ビシクロヌクレオシドの改良された製法 |
NZ531180A (en) | 1999-03-26 | 2005-06-24 | Aventis Pharma Inc | Compositions and methods for effecting the levels of cholesterol using the LIPG polypeptide |
EP1171617B1 (en) | 1999-04-08 | 2008-02-13 | Novartis Vaccines and Diagnostics, Inc. | Enhancement of the immune response for vaccine and gene therapy applications |
US6977295B2 (en) | 1999-04-21 | 2005-12-20 | Invitrogen Corporation | Locked nucleic acid hybrids and methods of use |
CN1349541A (zh) | 1999-05-04 | 2002-05-15 | 埃克西库恩公司 | L-核糖-lna类似物 |
US20030233670A1 (en) | 2001-12-04 | 2003-12-18 | Edgerton Michael D. | Gene sequences and uses thereof in plants |
US6525191B1 (en) | 1999-05-11 | 2003-02-25 | Kanda S. Ramasamy | Conformationally constrained L-nucleosides |
DE19925073C2 (de) | 1999-06-01 | 2001-07-19 | Stefan Weiss | Nucleinsäuremoleküle mit spezifischer Erkennung von nativem PrP·S··c·, Herstellung und Verwendung |
US6656730B1 (en) | 1999-06-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Oligonucleotides conjugated to protein-binding drugs |
EP1189940A2 (en) | 1999-06-25 | 2002-03-27 | Genset | A bap28 gene and protein |
US20040006031A1 (en) | 2002-07-02 | 2004-01-08 | Isis Pharmaceuticals Inc. | Antisense modulation of HMG-CoA reductase expression |
US6147200A (en) | 1999-08-19 | 2000-11-14 | Isis Pharmaceuticals, Inc. | 2'-O-acetamido modified monomers and oligomers |
EP1218411A4 (en) | 1999-09-20 | 2004-09-01 | Millennium Pharm Inc | SECRETED PROTEINS AND THEIR USES |
US6617442B1 (en) | 1999-09-30 | 2003-09-09 | Isis Pharmaceuticals, Inc. | Human Rnase H1 and oligonucleotide compositions thereof |
US6986988B2 (en) | 1999-10-06 | 2006-01-17 | Quark Biotech, Inc. | Method for enrichment of natural antisense messenger RNA |
WO2001025488A2 (en) | 1999-10-06 | 2001-04-12 | Quark Biotech, Inc. | Method for enrichment of natural antisense messenger rna |
WO2001051630A1 (en) | 2000-01-07 | 2001-07-19 | Baylor University | Antisense compositions and methods |
AU2001230913B2 (en) | 2000-01-14 | 2005-06-30 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Methanocarba cycloalkyl nucleoside analogues |
US6303374B1 (en) | 2000-01-18 | 2001-10-16 | Isis Pharmaceuticals Inc. | Antisense modulation of caspase 3 expression |
US20020055479A1 (en) | 2000-01-18 | 2002-05-09 | Cowsert Lex M. | Antisense modulation of PTP1B expression |
US6258600B1 (en) * | 2000-01-19 | 2001-07-10 | Isis Pharmaceuticals, Inc. | Antisense modulation of caspase 8 expression |
US6287860B1 (en) | 2000-01-20 | 2001-09-11 | Isis Pharmaceuticals, Inc. | Antisense inhibition of MEKK2 expression |
JP2001247459A (ja) | 2000-03-03 | 2001-09-11 | Oakland Uniservices Ltd | 癌の組み合わせ療法 |
US6936467B2 (en) | 2000-03-27 | 2005-08-30 | University Of Delaware | Targeted chromosomal genomic alterations with modified single stranded oligonucleotides |
CA2404780A1 (en) | 2000-03-27 | 2001-10-04 | University Of Delaware | Targeted chromosomal genomic alterations with modified single stranded oligonucleotides |
US7402434B2 (en) | 2000-05-08 | 2008-07-22 | Newman Stuart A | Splice choice antagonists as therapeutic agents |
US6287960B1 (en) | 2000-05-08 | 2001-09-11 | Motorola, Inc. | Self aligned dual inlaid patterning and etching |
WO2002062840A1 (en) | 2000-06-29 | 2002-08-15 | Pharma Pacific Pty. Ltd. | INTERFERON-α INDUCED GENE |
JP2004505047A (ja) | 2000-07-28 | 2004-02-19 | キャンサー・リサーチ・テクノロジー・リミテッド | 複合治療による癌治療 |
US7053199B2 (en) | 2000-08-29 | 2006-05-30 | Takeshi Imanishi | Nucleoside analogs and oligonucleotide derivatives containing these analogs |
EP1313768B1 (de) | 2000-09-02 | 2008-02-06 | Grünenthal GmbH | Antisense oligonukleotide gegen vr 1 |
US6444464B1 (en) | 2000-09-08 | 2002-09-03 | Isis Pharmaceuticals, Inc. | Antisense modulation of E2F transcription factor 2 expression |
AU2001289085A1 (en) | 2000-09-20 | 2002-04-02 | Isis Pharmaceuticals, Inc. | Antisense modulation of flip-c expression |
US20030186920A1 (en) | 2000-10-13 | 2003-10-02 | Sirois Martin G. | Antisense oligonucleotide directed toward mammalian vegf receptor genes and uses thereof |
US20030228618A1 (en) | 2000-11-24 | 2003-12-11 | Erez Levanon | Methods and systems for identifying naturally occurring antisense transcripts and methods, kits and arrays utilizing same |
US20050222029A1 (en) | 2001-01-04 | 2005-10-06 | Myriad Genetics, Incorporated | Compositions and methods for treating diseases |
US7423142B2 (en) | 2001-01-09 | 2008-09-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of anti-apoptotic genes |
WO2002068470A2 (en) | 2001-02-26 | 2002-09-06 | Pharma Pacific Pty Ltd | Interferon-alpha induced gene |
US20020147165A1 (en) | 2001-02-22 | 2002-10-10 | Isis Pharmaceuticals, Inc. | Antisense modulation of calreticulin expression |
AUPR497101A0 (en) | 2001-05-14 | 2001-06-07 | Queensland University Of Technology | Polynucleotides and polypeptides linked to cancer and/or tumorigenesi |
IL143379A (en) | 2001-05-24 | 2013-11-28 | Yissum Res Dev Co | Oligonucleotide against human ache isoform r and its uses |
US7053195B1 (en) | 2001-06-12 | 2006-05-30 | Syngenta Participatious Ag | Locked nucleic acid containing heteropolymers and related methods |
US20050019915A1 (en) | 2001-06-21 | 2005-01-27 | Bennett C. Frank | Antisense modulation of superoxide dismutase 1, soluble expression |
CA2453183C (en) | 2001-07-12 | 2016-05-10 | University Of Massachusetts | In vivo production of small interfering rnas that mediate gene silencing |
US7153954B2 (en) | 2001-07-12 | 2006-12-26 | Santaris Pharma A/S | Method for preparation of LNA phosphoramidites |
US7425545B2 (en) | 2001-07-25 | 2008-09-16 | Isis Pharmaceuticals, Inc. | Modulation of C-reactive protein expression |
US20030096772A1 (en) | 2001-07-30 | 2003-05-22 | Crooke Rosanne M. | Antisense modulation of acyl CoA cholesterol acyltransferase-2 expression |
US7259150B2 (en) | 2001-08-07 | 2007-08-21 | Isis Pharmaceuticals, Inc. | Modulation of apolipoprotein (a) expression |
CA2459347C (en) | 2001-09-04 | 2012-10-09 | Exiqon A/S | Locked nucleic acid (lna) compositions and uses thereof |
US6936589B2 (en) | 2001-09-28 | 2005-08-30 | Albert T. Naito | Parenteral delivery systems |
US20040214766A1 (en) | 2001-10-01 | 2004-10-28 | Kari Alitalo | VEGF-C or VEGF-D materials and methods for treatment of neuropathologies |
CN1635895A (zh) | 2001-10-10 | 2005-07-06 | 雀巢产品有限公司 | 具有降低的α-D-半乳糖苷酶活性的咖啡植物 |
US7125982B1 (en) | 2001-12-05 | 2006-10-24 | Frayne Consultants | Microbial production of nuclease resistant DNA, RNA, and oligo mixtures |
US6965025B2 (en) | 2001-12-10 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of connective tissue growth factor expression |
CA2365811A1 (en) | 2001-12-21 | 2003-06-21 | Institut De Cardiologie | A new gene therapy using antisense strategy to estrogen receptors (er .alpha. and/or er .beta.) to optimize vascular healing and cardioprotection after vascular injury |
KR20030056538A (ko) | 2001-12-28 | 2003-07-04 | 주식회사 웰진 | 리본형 안티센스 올리고뉴클레오티드에 의한 형질전이성장 인자-β1의 효과적 저해제 개발 |
US20030191075A1 (en) | 2002-02-22 | 2003-10-09 | Cook Phillip Dan | Method of using modified oligonucleotides for hepatic delivery |
US20050143357A1 (en) | 2002-02-25 | 2005-06-30 | Ake Pousette | Vitamin d upregulated protein 1 (vdup-) methods and uses thereof |
WO2003077215A2 (en) | 2002-03-08 | 2003-09-18 | Glen Research Corporation | Fluorescent nitrogenous base and nucleosides incorporating same |
GB2386836B (en) | 2002-03-22 | 2006-07-26 | Cancer Res Ventures Ltd | Anti-cancer combinations |
US7169916B2 (en) | 2002-04-01 | 2007-01-30 | Isis Pharmaceuticals, Inc. | Chloral-free DCA in oligonucleotide synthesis |
US20050215504A1 (en) | 2002-04-02 | 2005-09-29 | Bennett C F | Antisense modulation of sterol regulatory element-binding protein-1 expression |
CA2480311C (en) | 2002-04-05 | 2015-01-27 | Santaris Pharma A/S | Oligomeric compounds for the modulation of hif-1alpha expression |
US7569575B2 (en) | 2002-05-08 | 2009-08-04 | Santaris Pharma A/S | Synthesis of locked nucleic acid derivatives |
US6808906B2 (en) | 2002-05-08 | 2004-10-26 | Rigel Pharmaceuticals, Inc. | Directionally cloned random cDNA expression vector libraries, compositions and methods of use |
US7199107B2 (en) | 2002-05-23 | 2007-04-03 | Isis Pharmaceuticals, Inc. | Antisense modulation of kinesin-like 1 expression |
US7148342B2 (en) | 2002-07-24 | 2006-12-12 | The Trustees Of The University Of Pennyslvania | Compositions and methods for sirna inhibition of angiogenesis |
US20040033480A1 (en) | 2002-08-15 | 2004-02-19 | Wong Norman C.W. | Use of resveratrol to regulate expression of apolipoprotein A1 |
NZ538259A (en) | 2002-09-10 | 2008-03-28 | Samuel Roberts Noble Found Inc | Methods and compositions for production of flavonoid and isoflavonoid nutraceuticals |
AU2003283966A1 (en) | 2002-09-25 | 2004-04-23 | Pharmacia Corporation | Antisense modulation of farnesoid x receptor expression |
EP2272958A1 (en) | 2002-09-26 | 2011-01-12 | ISIS Pharmaceuticals, Inc. | Modulation of forkhead box O1A expression |
AU2003291678B2 (en) | 2002-11-01 | 2009-01-15 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of HIF-1 alpha |
US20040152651A1 (en) | 2002-11-01 | 2004-08-05 | Rana Tariq M. | Regulation of transcription elongation factors |
GB2394658A (en) | 2002-11-01 | 2004-05-05 | Cancer Rec Tech Ltd | Oral anti-cancer composition |
US7892793B2 (en) | 2002-11-04 | 2011-02-22 | University Of Massachusetts | Allele-specific RNA interference |
AU2003291755A1 (en) | 2002-11-05 | 2004-06-07 | Isis Pharmaceuticals, Inc. | Oligomers comprising modified bases for binding cytosine and uracil or thymine and their use |
WO2004041889A2 (en) | 2002-11-05 | 2004-05-21 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US20060009410A1 (en) | 2002-11-13 | 2006-01-12 | Crooke Rosanne M | Effects of apolipoprotein B inhibition on gene expression profiles in animals |
DK1569661T3 (da) | 2002-11-18 | 2010-01-11 | Santaris Pharma As | Antisense design |
US7144999B2 (en) | 2002-11-23 | 2006-12-05 | Isis Pharmaceuticals, Inc. | Modulation of hypoxia-inducible factor 1 alpha expression |
US7713738B2 (en) | 2003-02-10 | 2010-05-11 | Enzon Pharmaceuticals, Inc. | Oligomeric compounds for the modulation of survivin expression |
US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
US7339051B2 (en) | 2003-04-28 | 2008-03-04 | Isis Pharmaceuticals, Inc. | Compositions and methods for the treatment of severe acute respiratory syndrome (SARS) |
CA2540692C (en) | 2003-06-02 | 2013-05-28 | Isis Pharmaceuticals, Inc. | Oligonucleotide synthesis with alternative solvents |
JP4579911B2 (ja) | 2003-06-03 | 2010-11-10 | アイシス・ファーマシューティカルズ・インコーポレイテッド | スルビビン発現の調節 |
US7825235B2 (en) | 2003-08-18 | 2010-11-02 | Isis Pharmaceuticals, Inc. | Modulation of diacylglycerol acyltransferase 2 expression |
EP2182063A3 (en) | 2003-09-18 | 2012-07-18 | Isis Pharmaceuticals, Inc. | Modulation of EIF4E expression |
WO2005038013A1 (en) | 2003-10-07 | 2005-04-28 | Isis Pharmaceuticals, Inc. | Artisense oligonucleotides optimized for kidney targeting |
EP1675948A2 (en) | 2003-10-23 | 2006-07-05 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED TREATMENT OF PARKINSON DISEASE USING SHORT INTERERING NUCLEIC ACID (siNA) |
RU2377301C2 (ru) | 2003-12-23 | 2009-12-27 | Сантарис Фарма А/С | ОЛИГОМЕРНОЕ СОЕДИНЕНИЕ, ПОНИЖАЮЩЕЕ ЭКСПРЕССИЮ ЧЕЛОВЕЧЕСКОГО ГЕНА Bcl-2, КОНЪЮГАТ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И ПРИМЕНЕНИЕ ОЛИГОМЕРНОГО СОЕДИНЕНИЯ ДЛЯ ЛЕЧЕНИЯ РАКА |
JP4801802B2 (ja) | 2004-01-12 | 2011-10-26 | ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア | 特定の選択的な電気信号および電磁信号によって生成される電場の印加を介して骨細胞における骨形成タンパク質(bmp)遺伝子発現を上方制御するシステムおよび方法 |
US7468431B2 (en) | 2004-01-22 | 2008-12-23 | Isis Pharmaceuticals, Inc. | Modulation of eIF4E-BP2 expression |
GB0403041D0 (en) | 2004-02-11 | 2004-03-17 | Milner Anne J | Induction of apoptosis |
EP1566202A1 (en) | 2004-02-23 | 2005-08-24 | Sahltech I Göteborg AB | Use of resistin antagonists in the treatment of rheumatoid arthritis |
JP4144876B2 (ja) * | 2004-03-04 | 2008-09-03 | 独立行政法人科学技術振興機構 | Hiv−1複製抑制剤 |
US7402574B2 (en) | 2004-03-12 | 2008-07-22 | Avi Biopharma, Inc. | Antisense composition and method for treating cancer |
US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
US7297786B2 (en) | 2004-07-09 | 2007-11-20 | University Of Iowa Research Foundation | RNA interference in respiratory epitheial cells |
WO2006023880A2 (en) | 2004-08-23 | 2006-03-02 | Isis Pharmaceuticals, Inc. | Compounds and methods for the characterization of oligonucleotides |
US7589190B2 (en) | 2004-11-09 | 2009-09-15 | Enzon Pharmaceuticals, Inc. | Potent LNA oligonucleotides for the inhibition of HIF-1A expression |
US7220549B2 (en) | 2004-12-30 | 2007-05-22 | Helicos Biosciences Corporation | Stabilizing a nucleic acid for nucleic acid sequencing |
JP5116107B2 (ja) | 2005-06-27 | 2013-01-09 | アルナイラム ファーマシューティカルズ, インコーポレイテッド | HIF−1のRNAi調節及びその治療的利用 |
US20070213292A1 (en) | 2005-08-10 | 2007-09-13 | The Rockefeller University | Chemically modified oligonucleotides for use in modulating micro RNA and uses thereof |
WO2007028065A2 (en) | 2005-08-30 | 2007-03-08 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds for modulation of splicing |
CA2627025A1 (en) | 2005-10-28 | 2007-05-03 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of huntingtin gene |
WO2007056326A2 (en) | 2005-11-04 | 2007-05-18 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of nav1.8 gene |
EP2431467A3 (en) | 2005-11-17 | 2012-05-02 | Board Of Regents, The University Of Texas | Modulation of gene expression by oligomers targeted to chromosomal DNA |
CN101374964B (zh) | 2005-12-09 | 2013-07-17 | 贝勒研究院 | 外周血液白细胞转录模式的模块水平分析 |
CN100356377C (zh) | 2005-12-20 | 2007-12-19 | 无锡永中科技有限公司 | 文档显示方法 |
WO2007071824A1 (en) | 2005-12-20 | 2007-06-28 | Oy Jurilab Ltd | Novel genes and markers associated with high-density lipoprotein -cholesterol (hdl-c) |
JP2009524430A (ja) | 2006-01-26 | 2009-07-02 | ユニバーシティ オブ マサチューセッツ | 治療的使用のためのrna干渉剤 |
US7569686B1 (en) | 2006-01-27 | 2009-08-04 | Isis Pharmaceuticals, Inc. | Compounds and methods for synthesis of bicyclic nucleic acid analogs |
KR20130042043A (ko) | 2006-01-27 | 2013-04-25 | 아이시스 파마수티컬즈 인코포레이티드 | 6-변형된 바이시클릭 핵산 유사체 |
WO2007085485A2 (en) * | 2006-01-27 | 2007-08-02 | Santaris Pharma A/S | Lna modified phosphorothiolated oligonucleotides |
KR101462874B1 (ko) | 2006-03-31 | 2014-11-18 | 알닐람 파마슈티칼스 인코포레이티드 | Eg5 유전자의 발현을 억제하는 이본쇄 리보핵산 |
WO2007131238A2 (en) | 2006-05-05 | 2007-11-15 | Isis Pharmaceuticals , Inc. | Compounds and methods for modulating expression apob |
US7666854B2 (en) | 2006-05-11 | 2010-02-23 | Isis Pharmaceuticals, Inc. | Bis-modified bicyclic nucleic acid analogs |
JP5441688B2 (ja) | 2006-05-11 | 2014-03-12 | アイシス ファーマシューティカルズ, インコーポレーテッド | 5’修飾二環式核酸類似体 |
EP2584048B1 (en) | 2006-05-11 | 2014-07-23 | Alnylam Pharmaceuticals Inc. | Compositions and methods for inhibiting expression of the PCSK9 gene |
EP1867338A1 (en) | 2006-05-30 | 2007-12-19 | Université Libre De Bruxelles | Pharmaceutical composition comprising apolipoproteins for the treatment of human diseases |
WO2008066672A2 (en) | 2006-11-06 | 2008-06-05 | Beth Israel Deaconess Medical Center | Identification and use of small molecules to modulate transcription factor function and to treat transcription factor associated diseases |
WO2008057556A2 (en) | 2006-11-06 | 2008-05-15 | Beth Israel Deaconess Medical Center | Identification and use of small molecules to modulate ese-1 transcription factor function and to treat ese-1 transcription factor associated diseases |
US8093222B2 (en) | 2006-11-27 | 2012-01-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
US20100169996A1 (en) | 2007-01-19 | 2010-07-01 | Lionel Navarro | Methods and compositions for modulating the sirna and rna-directed-dna methylation pathways |
CA2686933A1 (en) | 2007-04-06 | 2008-10-16 | The Johns Hopkins University | Methods and compositions for the treatment of cancer |
US20080293142A1 (en) | 2007-04-19 | 2008-11-27 | The Board Of Regents For Oklahoma State University | Multiple shRNA Expression Vectors and Methods of Construction |
WO2009044793A1 (ja) | 2007-10-02 | 2009-04-09 | Alphagen Co., Ltd. | 癌遺伝子を標的とするsiRNA |
JP5093484B2 (ja) * | 2008-03-04 | 2012-12-12 | 独立行政法人産業技術総合研究所 | 低比重リポ蛋白質受容体の発現増強剤 |
EP2924118A1 (en) | 2008-07-01 | 2015-09-30 | Monsanto Technology LLC | Recombinant DNA constructs and methods for modulating expression of a target gene |
ES2727549T3 (es) | 2008-10-03 | 2019-10-17 | Curna Inc | Tratamiento de las enfermedades relacionadas con la apolipoproteína a1 por inhibición del transcrito antisentido natural a la apolipoproteína a1 |
EP2177615A1 (en) | 2008-10-10 | 2010-04-21 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Method for a genome wide identification of expression regulatory sequences and use of genes and molecules derived thereof for the diagnosis and therapy of metabolic and/or tumorous diseases |
US8606289B2 (en) | 2008-11-10 | 2013-12-10 | Qualcomm Incorporated | Power headroom-sensitive scheduling |
JP2012509306A (ja) | 2008-11-22 | 2012-04-19 | ザ ユニバーシティ オブ ブリストル | VEGFxxxbの新規な使用 |
WO2013080784A1 (ja) | 2011-11-30 | 2013-06-06 | シャープ株式会社 | メモリ回路とその駆動方法、及び、これを用いた不揮発性記憶装置、並びに、液晶表示装置 |
-
2010
- 2010-05-06 JP JP2012509965A patent/JP6250930B2/ja not_active Expired - Fee Related
- 2010-05-06 US US13/318,700 patent/US20120046236A1/en not_active Abandoned
- 2010-05-06 EP EP10772814.9A patent/EP2427552B1/en active Active
- 2010-05-06 CA CA2761142A patent/CA2761142C/en active Active
- 2010-05-06 CN CN201080027720.7A patent/CN102803492B/zh active Active
- 2010-05-06 WO PCT/US2010/033836 patent/WO2010129746A2/en active Application Filing
- 2010-05-06 KR KR1020117028464A patent/KR101722541B1/ko not_active Expired - Fee Related
- 2010-05-06 ES ES10772814.9T patent/ES2609655T3/es active Active
-
2013
- 2013-12-24 US US14/140,305 patent/US9163285B2/en active Active
-
2015
- 2015-09-09 US US14/848,948 patent/US9611477B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1602427A (zh) * | 2001-12-12 | 2005-03-30 | 默克专利股份公司 | 三重四脯氨酸碱性蛋白用于保护心脏避免发生心脏损伤的抑制作用 |
WO2004044202A1 (en) * | 2002-11-14 | 2004-05-27 | Toolgen, Inc. | Method for the gene regulation at both transcription and post-transcription levels |
CN1798579A (zh) * | 2003-04-01 | 2006-07-05 | 因特拉迪格姆公司 | 肿瘤生长抑制的目标 |
US20070248590A1 (en) * | 2005-12-02 | 2007-10-25 | Sirtris Pharmaceuticals, Inc. | Modulators of CDC2-like kinases (CLKS) and methods of use thereof |
WO2007087113A2 (en) * | 2005-12-28 | 2007-08-02 | The Scripps Research Institute | Natural antisense and non-coding rna transcripts as drug targets |
Non-Patent Citations (4)
Title |
---|
Accession Number AY771351;Livingston R. J.等;《GenBank》;20041018 * |
Atherosclerotic Ploaque Macrophage Transcriptional Regulators Are Expressed in Blood and Modulated by tristetraprolin;Willmar D. Patino等;《Circulation Research》;20061231;1282-1289 * |
Interactions of CCCH zinc finger proteins with mRNA tristetraprolin-mediated AU-rich element-dependent mRNA degradation can occur in the absence of a polyA tail;Lai W S等;《J Biol Chem》;20011231;23144-23154 * |
Phosphorylation site analysis of the anti-inflanmatory and mRNA-destabilizing protein tristetraprolin;Cao H等;《Expert Rev Proteomics》;20071231;7117-726 * |
Also Published As
Publication number | Publication date |
---|---|
CA2761142C (en) | 2021-06-08 |
KR101722541B1 (ko) | 2017-04-04 |
JP6250930B2 (ja) | 2017-12-20 |
CN102803492A (zh) | 2012-11-28 |
EP2427552A4 (en) | 2013-06-05 |
ES2609655T3 (es) | 2017-04-21 |
EP2427552A2 (en) | 2012-03-14 |
CA2761142A1 (en) | 2010-11-11 |
JP2012525849A (ja) | 2012-10-25 |
US20140155464A1 (en) | 2014-06-05 |
US9611477B2 (en) | 2017-04-04 |
WO2010129746A2 (en) | 2010-11-11 |
WO2010129746A3 (en) | 2011-07-21 |
KR20120057574A (ko) | 2012-06-05 |
US9163285B2 (en) | 2015-10-20 |
EP2427552B1 (en) | 2016-11-16 |
US20160010092A1 (en) | 2016-01-14 |
US20120046236A1 (en) | 2012-02-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102803492B (zh) | 通过抑制针对三重四脯氨酸(ttp)的天然反义转录物来治疗ttp相关疾病 | |
CN102387817B (zh) | 通过抑制针对脑衍生神经营养因子(bdnf)的天然反义转录物来治疗bdnf相关的疾病 | |
CN102307997B (zh) | 通过抑制针对沉默调节蛋白1的天然反义转录物来治疗沉默调节蛋白1(sirt1)相关的疾病 | |
CN102341498B (zh) | 通过抑制血管内皮生长因子(vegf)的天然反义转录子治疗vegf相关的疾病 | |
CN102239260B (zh) | 通过抑制针对载脂蛋白‑a1的天然反义转录物治疗载脂蛋白‑a1相关疾病 | |
CN102639151B (zh) | 通过针对hbf/hbg的天然反义转录物的抑制治疗血红蛋白(hbf/hbg)相关疾病 | |
CN103221541B (zh) | 通过抑制抗病毒基因的天然反义转录物来治疗抗病毒基因相关疾病 | |
CN102361985B (zh) | 通过抑制肿瘤抑制基因的天然反义转录物治疗肿瘤抑制基因相关性疾病 | |
CN102439149B (zh) | 通过抑制针对胶质细胞衍生神经营养因子(gdnf)的天然反义转录物来治疗gdnf相关的疾病 | |
CN102549158B (zh) | 通过抑制针对转录因子e3(tfe3)的天然反义转录物来治疗tfe3和胰岛素受体底物蛋白2(irs2)相关的疾病 | |
CN102906264B (zh) | 通过抑制干扰素调节因子8(irf8)的天然反义转录物而治疗irf8相关疾病 | |
CN102712927B (zh) | 通过抑制膜结合转录因子肽酶,位点1(mbtps1)的天然反义转录物来治疗mbtps1相关疾病 | |
CN102597238B (zh) | 通过抑制针对肿瘤坏死因子受体2(tnfr2)的天然反义转录物来治疗tnfr2相关的疾病 | |
CN102844435B (zh) | 通过抑制吡咯啉‑5‑羧酸还原酶1(pycr1)的天然反义转录物而治疗pycr1相关疾病 | |
CN102459596B (zh) | 通过针对脂质转运和代谢基因的天然反义转录物的抑制治疗脂质转运和代谢基因相关疾病 | |
CN102858979B (zh) | 通过抑制成纤维细胞生长因子21(fgf21)的天然反义转录物而治疗fgf21相关疾病 | |
CN102612560B (zh) | 通过抑制针对对氧磷酶1(pon1)的天然反义转录物来治疗pon1相关的疾病 | |
CN102762731B (zh) | 通过抑制针对胰岛素基因(ins)的天然反义转录物来治疗胰岛素基因(ins)相关的疾病 | |
CN102782135A (zh) | 通过抑制rna酶h1的天然反义转录物而治疗rna酶h1相关疾病 | |
CN102781480A (zh) | 通过抑制解偶联蛋白2(ucp2)的天然反义转录物而治疗ucp2相关疾病 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |