JP2022017227A - Pcsk9を標的としたアンチセンス核酸 - Google Patents
Pcsk9を標的としたアンチセンス核酸 Download PDFInfo
- Publication number
- JP2022017227A JP2022017227A JP2021154910A JP2021154910A JP2022017227A JP 2022017227 A JP2022017227 A JP 2022017227A JP 2021154910 A JP2021154910 A JP 2021154910A JP 2021154910 A JP2021154910 A JP 2021154910A JP 2022017227 A JP2022017227 A JP 2022017227A
- Authority
- JP
- Japan
- Prior art keywords
- group
- base sequence
- oligonucleotide
- carbon atoms
- seq
- 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.)
- Granted
Links
- 150000007523 nucleic acids Chemical class 0.000 title abstract description 72
- 102000039446 nucleic acids Human genes 0.000 title abstract description 71
- 108020004707 nucleic acids Proteins 0.000 title abstract description 71
- 230000000692 anti-sense effect Effects 0.000 title abstract description 59
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 104
- 230000027455 binding Effects 0.000 claims abstract description 38
- 230000000694 effects Effects 0.000 claims abstract description 36
- 239000002777 nucleoside Substances 0.000 claims abstract description 35
- 238000008214 LDL Cholesterol Methods 0.000 claims abstract description 28
- 230000014509 gene expression Effects 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 22
- 101100135844 Homo sapiens PCSK9 gene Proteins 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 14
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 12
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 claims abstract description 11
- 108010006523 asialoglycoprotein receptor Proteins 0.000 claims abstract description 11
- 230000000295 complement effect Effects 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 70
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 claims description 35
- 108020003175 receptors Proteins 0.000 claims description 35
- 102000005962 receptors Human genes 0.000 claims description 35
- 125000005647 linker group Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000003835 nucleoside group Chemical group 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 12
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 230000000069 prophylactic effect Effects 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose 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)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- FVMMQJUBNMOPPR-WLDMJGECSA-N N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]formamide Chemical compound OC[C@H]1OC(O)[C@H](NC=O)[C@@H](O)[C@H]1O FVMMQJUBNMOPPR-WLDMJGECSA-N 0.000 claims description 3
- RTEOJYOKWPEKKN-HXQZNRNWSA-N N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]propanamide Chemical compound CCC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O RTEOJYOKWPEKKN-HXQZNRNWSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 3
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 3
- 229930182830 galactose Natural products 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- KXTUJUVCAGXOBN-WQXQQRIOSA-N 2-methyl-N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]propanamide Chemical compound CC(C)C(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O KXTUJUVCAGXOBN-WQXQQRIOSA-N 0.000 claims description 2
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 abstract description 35
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 abstract description 30
- 238000001727 in vivo Methods 0.000 abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
- 238000011161 development Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 108010002913 Asialoglycoproteins Proteins 0.000 description 35
- 238000012360 testing method Methods 0.000 description 31
- 239000008280 blood Substances 0.000 description 29
- 210000004369 blood Anatomy 0.000 description 29
- -1 small molecule compound Chemical class 0.000 description 25
- 238000000034 method Methods 0.000 description 21
- 238000010586 diagram Methods 0.000 description 18
- 241000282567 Macaca fascicularis Species 0.000 description 17
- 108020004999 messenger RNA Proteins 0.000 description 16
- 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 13
- 235000000346 sugar Nutrition 0.000 description 13
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000002773 nucleotide Substances 0.000 description 11
- 125000003729 nucleotide group Chemical group 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000000074 antisense oligonucleotide Substances 0.000 description 8
- 238000012230 antisense oligonucleotides Methods 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 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 8
- 238000011282 treatment Methods 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 102000053602 DNA Human genes 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 6
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 6
- 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 6
- 229940109239 creatinine Drugs 0.000 description 6
- 201000001386 familial hypercholesterolemia Diseases 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 102000053786 human PCSK9 Human genes 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 230000002485 urinary effect Effects 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 108010007622 LDL Lipoproteins Proteins 0.000 description 4
- 102000007330 LDL Lipoproteins Human genes 0.000 description 4
- 101150094724 PCSK9 gene Proteins 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 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 4
- 108091028664 Ribonucleotide Proteins 0.000 description 4
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000002336 ribonucleotide Substances 0.000 description 4
- 125000002652 ribonucleotide group Chemical group 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000002562 urinalysis Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 0 CC[C@@](C#CCC*=C=*)OP(O)(O[C@](C[C@]1C*P(*)(O[C@]2CN(C3OC3CCCCO[C@](*C(CO)[C@@](C3O)O)C3NC(C)=O)[C@](COP(*)(O[C@](C[C@]3CO)CN3C(CCCC*[C@@](C(C3O)NC(C)=O)OC(CO)[C@]3O)=O)=O)C2)=O)CN1C(CCCCO[C@@](C(C1O)NC(C)=O)OC(CO)[C@@]1O)=O)=* Chemical compound CC[C@@](C#CCC*=C=*)OP(O)(O[C@](C[C@]1C*P(*)(O[C@]2CN(C3OC3CCCCO[C@](*C(CO)[C@@](C3O)O)C3NC(C)=O)[C@](COP(*)(O[C@](C[C@]3CO)CN3C(CCCC*[C@@](C(C3O)NC(C)=O)OC(CO)[C@]3O)=O)=O)C2)=O)CN1C(CCCCO[C@@](C(C1O)NC(C)=O)OC(CO)[C@@]1O)=O)=* 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 108010028554 LDL Cholesterol Proteins 0.000 description 3
- 108010001831 LDL receptors Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 238000010876 biochemical test Methods 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000005547 deoxyribonucleotide Substances 0.000 description 3
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 210000004738 parenchymal cell Anatomy 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 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 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000004665 fatty acids Chemical group 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 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
- 125000000524 functional group Chemical group 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 150000002390 heteroarenes Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000008300 phosphoramidites Chemical class 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000009528 severe injury Effects 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- QGVQZRDQPDLHHV-DPAQBDIFSA-N (3s,8s,9s,10r,13r,14s,17r)-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]phenanthrene-3-thiol Chemical compound C1C=C2C[C@@H](S)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 QGVQZRDQPDLHHV-DPAQBDIFSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OBDUMNZXAIUUTH-HWKANZROSA-N (e)-tetradec-2-ene Chemical group CCCCCCCCCCC\C=C\C OBDUMNZXAIUUTH-HWKANZROSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- BFGRUUKLRZUPBB-DTZZCLTHSA-N 1-[(3R,4R,5R,6R)-3-amino-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]butan-1-one Chemical compound C(CCC)(=O)C1(O)[C@H](N)[C@@H](O)[C@@H](O)[C@H](O1)CO BFGRUUKLRZUPBB-DTZZCLTHSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006028 1-methyl-2-butenyl group Chemical group 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical group CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003890 2-phenylbutyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000008102 Ankyrins Human genes 0.000 description 1
- 108010049777 Ankyrins Proteins 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- PUQGNPYLXFGYJG-VPONPHJJSA-N CCC(CNC(CCCCO[C@@H](C(C1O)NC(C)=O)OC(CO)[C@@H]1O)=O)OP(O)(OCC(CNC(CCCCO[C@@H](C(C1O)NC(C)=O)OC(CO)[C@@H]1O)=O)O)=O Chemical compound CCC(CNC(CCCCO[C@@H](C(C1O)NC(C)=O)OC(CO)[C@@H]1O)=O)OP(O)(OCC(CNC(CCCCO[C@@H](C(C1O)NC(C)=O)OC(CO)[C@@H]1O)=O)O)=O PUQGNPYLXFGYJG-VPONPHJJSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 1
- 101710185991 Hepatitis A virus cellular receptor 1 homolog Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-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
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical class CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 1
- 229930182474 N-glycoside Natural products 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229940122392 PCSK9 inhibitor Drugs 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000002617 apheresis Methods 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 229930195729 fatty acid Chemical group 0.000 description 1
- 239000000194 fatty acid Chemical group 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 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 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 150000002341 glycosylamines Chemical class 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000007489 histopathology method Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000006301 indolyl methyl group Chemical group 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 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
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000008627 kidney hypertrophy Diseases 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004706 n-propylthio group Chemical group C(CC)S* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 108091008104 nucleic acid aptamers Proteins 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method 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
- 235000009566 rice Nutrition 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011782 vitamin Chemical group 0.000 description 1
- 229930003231 vitamin Chemical group 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
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
- C12N15/1137—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 against enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- 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
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21112—Site-1 protease (3.4.21.112), i.e. subtilisin kexin isozyme-1
-
- 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
- C12N2310/315—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
- C12N2310/323—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
-
- 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
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/341—Gapmers, i.e. of the type ===---===
-
- 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
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
-
- 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
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
-
- 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
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3515—Lipophilic moiety, e.g. cholesterol
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Diabetes (AREA)
- Physics & Mathematics (AREA)
- Virology (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
〔1〕 4’位と2’位との間に架橋構造を有する架橋型人工ヌクレオシドを含み、ヒトPCSK9遺伝子と相補的であり、該ヒトPCSK9遺伝子の発現を抑制する活性を有するオリゴヌクレオチドに、アシアロ糖蛋白質受容体に結合し得る分子が直鎖状に2個以上連結して結合してなる、オリゴヌクレオチドコンジュゲート体。
〔2〕 架橋構造が下記(i)~(iv)から選ばれる、前記〔1〕記載のオリゴヌクレオチドコンジュゲート体。
(i) -CH2-O-又は-(CH2)2-O-で表される構造
(ii) -CH2-NR1-O-又は-(CH2)2-NR1-O-で表される構造
(iii) -CO-NR1-、-CH2-CO-NR1-、-(CH2)2-CO-NR1-、-CO-NR1-X-又は-CH2-CO-NR1-X-で表される構造
(iv) -CH2-NR1-又は-(CH2)2-NR1-で表される構造
(ここで、R1は、水素原子;
分岐又は環を形成していてもよい炭素数1から7のアルキル基;
分岐又は環を形成していてもよい炭素数2から7のアルケニル基;
水酸基、炭素数1から6の直鎖アルキル基、炭素数1から6の直鎖アルコキシ基、メルカプト基、炭素数1から6の直鎖アルキルチオ基、アミノ基、炭素数1から6の直鎖アルキルアミノ基及びハロゲン原子からなるα群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール基;あるいは
該α群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール部分を有するアルキル基を表し、
Xは、酸素原子、硫黄原子、アミノ基又はメチレン基を表す)
〔3〕 ヒトPCSK9遺伝子が、以下の塩基配列:
配列番号3で示される塩基配列;配列番号4で示される塩基配列;配列番号5で示される塩基配列;配列番号6で示される塩基配列;配列番号7で示される塩基配列;配列番号8で示される塩基配列;配列番号9で示される塩基配列;配列番号10で示される塩基配列;配列番号11で示される塩基配列;配列番号12で示される塩基配列;配列番号13で示される塩基配列;配列番号14で示される塩基配列
又はこれらに相補的な塩基配列のいずれかを含む塩基配列からなる領域である、前記〔1〕又は〔2〕記載のオリゴヌクレオチドコンジュゲート体。
〔4〕 ヌクレオシド間の1又は2以上の結合がホスホロチオエート結合である、前記〔1〕~〔3〕いずれか記載のオリゴヌクレオチドコンジュゲート体。
〔5〕 アシアロ糖蛋白質受容体に結合し得る分子同士の間及びオリゴヌクレオチドとアシアロ糖蛋白質受容体に結合し得る分子との間から選ばれる1又は2以上の結合がホスホジエステル結合である、前記〔1〕~〔4〕いずれか記載のオリゴヌクレオチドコンジュゲート体。
〔6〕 オリゴヌクレオチドとアシアロ糖蛋白質受容体に結合し得る分子との間の結合が下記から選ばれるリンカーを介した結合である、前記〔1〕~〔5〕いずれか記載のオリゴヌクレオチドコンジュゲート体。
〔8〕 アシアロ糖蛋白質受容体に結合し得る分子が、ラクトース、ガラクトース、N-アセチルガラクトサミン(GalNAc)、ガラクトサミン、N-ホルミルガラクトサミン、N-プロピオニルガラクトサミン、N-n-ブタノイルガラクトサミン、N-イソ-ブタノイルガラクトサミン及びそれらの誘導体からなる群より選ばれる1種又は2種以上である、前記〔1〕~〔7〕いずれか記載のオリゴヌクレオチドコンジュゲート体。
〔9〕 オリゴヌクレオチドの塩基配列の長さが10~25塩基である、前記〔1〕~〔8〕いずれか記載のオリゴヌクレオチドコンジュゲート体。
〔10〕 前記〔1〕~〔9〕いずれか記載のオリゴヌクレオチドコンジュゲート体を有効成分として含有する、LDLコレステロールの高値が関連する疾患の予防又は治療剤。
〔11〕 LDLコレステロールの高値が関連する疾患が、高コレステロール血症及びLDLコレステロールの低下がより必要である高いリスクを有する疾患から選ばれる、前記〔10〕記載の予防又は治療剤。
〔12〕 注射剤である、前記〔10〕又は〔11〕記載の予防又は治療剤。
水素原子;
分岐又は環を形成していてもよい炭素数1から7のアルキル基;
分岐又は環を形成していてもよい炭素数2から7のアルケニル基;
水酸基、炭素数1から6の直鎖アルキル基、炭素数1から6の直鎖アルコキシ基、メルカプト基、炭素数1から6の直鎖アルキルチオ基、アミノ基、炭素数1から6の直鎖アルキルアミノ基及びハロゲン原子からなるα群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール基;あるいは
該α群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール部分を有するアルキル基
を表す。このような架橋構造を以下、態様2の架橋構造(BNANC)という場合がある。
水素原子;
分岐又は環を形成していてもよい炭素数1から7のアルキル基;
分岐又は環を形成していてもよい炭素数2から7のアルケニル基;
水酸基、炭素数1から6の直鎖アルキル基、炭素数1から6の直鎖アルコキシ基、メルカプト基、炭素数1から6の直鎖アルキルチオ基、アミノ基、炭素数1から6の直鎖アルキルアミノ基及びハロゲン原子からなるα群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール基;あるいは
該α群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール部分を有するアルキル基を表し、
Xは、酸素原子、硫黄原子、アミノ基又はメチレン基
を表す。このような架橋構造を以下、態様3の架橋構造(AmNA)という場合がある。
水素原子;
分岐又は環を形成していてもよい炭素数1から7のアルキル基;
分岐又は環を形成していてもよい炭素数2から7のアルケニル基;
水酸基、炭素数1から6の直鎖アルキル基、炭素数1から6の直鎖アルコキシ基、メルカプト基、炭素数1から6の直鎖アルキルチオ基、アミノ基、炭素数1から6の直鎖アルキルアミノ基及びハロゲン原子からなるα群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール基;あるいは
該α群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール部分を有するアルキル基
を表す。このような架橋構造を以下、態様4の架橋構造という場合がある。
配列番号3で示される塩基配列;配列番号4で示される塩基配列;配列番号5で示される塩基配列;配列番号6で示される塩基配列;配列番号7で示される塩基配列;配列番号8で示される塩基配列;配列番号9で示される塩基配列;配列番号10で示される塩基配列;配列番号11で示される塩基配列;配列番号12で示される塩基配列;配列番号13で示される塩基配列;配列番号14で示される塩基配列
又はこれらに相補的な塩基配列のいずれかを含む塩基配列が挙げられる。より好適には、これらの塩基配列からなるDNA又はRNAである。
(I)本発明のオリゴヌクレオチドコンジュゲート体を投与する工程を有する、LDLコレステロールの高値が関連する疾患を治療する方法
(II)LDLコレステロールの高値が関連する疾患の治療に用いられる、本発明のオリゴヌクレオチドコンジュゲート体の使用
(III)LDLコレステロールの高値が関連する疾患の治療剤の製造に用いられる、本発明のオリゴヌクレオチドコンジュゲート体の使用
ヒト肝がん由来細胞株Huh-7をプレートに播種し、DMEM(10%FBS、1%penicillin、1%streptomycin)にて24時間培養後、培地をCEM(DMEM含有:10%FBS、1%penicillin、1%streptomycin、9mM CaCl2)に各アンチセンスを200nMとなるように添加した培養液に置換した。その24時間後、total RNAを抽出し、cDNAを作成し、StepOnePlus(登録商標)リアルタイムPCRシステム(ABI社)にて以下のプローブを用いてPCSK9 mRNA及びGAPDH mRNAの発現量を定量し、PCSK9 mRNAの相対発現量を算出した。なお、各アンチセンスは、ヒトPCSK9遺伝子の塩基配列から選択したものに、架橋構造として「LNA(4’-CH2-O-2’)」又は「AmNA(4’-CO-NCH3-2’)」が導入されたものを公知の方法に従って作製して用いた。結果を図1に示す。
PCSK9 : Hs00545399_m1(ThermoFisher社 品番4331182)
GAPDH : Hs02786624_g1(ThermoFisher社 品番4331182)
ヒト肝がん由来細胞株Huh-7をプレートに播種し、DMEM(10%FBS、1%penicillin、1%streptomycin)にて24時間培養後、培地をCEM(DMEM含有:10%FBS、1%penicillin、1%streptomycin、9mM CaCl2)に試験例1のスクリーニングにより選んだアンチセンス(AmNA架橋構造を有するもの)を終濃度8~200nMとなるように添加した培養液に置換した。その24時間後、total RNAを抽出し、cDNAを作成し、StepOnePlus(登録商標)リアルタイムPCRシステム(ABI社)、SYBR Green(Fast SYBR(登録商標)Green Master Mix)を用いて試験例1と同じプローブを用いてPCSK9 mRNAの相対発現量を算出した。結果を図2に示す。
高脂血症カニクイザルを用いて、HsPCSK9-1811(配列番号14)のLNA架橋構造を有するものとAmNA架橋構造を有するものについて、薬効を評価した。
カニクイザルを用いて、HsPCSK9-1811(配列番号14)のLNA架橋構造を有するものを用いて安全性評価を実施した。
ラットを用いて、HsPCSK9-1811(配列番号14)のLNA架橋構造を有するものを用いて予備毒性試験を実施した。
試験例4及び試験例5にて腎障害の認められたHsPCSK9-1811(配列番号14)のLNA架橋構造を有するものに対してホスホロアミダイト法により単量体GalNAcユニット(GalNAcアミダイト体)を核酸自動合成機(OligoPilot10、GEヘルスケア社)にて3ユニット連続導入し、アンチセンス核酸GalNAcコンジュゲート体[HsPCSK9-1811-LNA(14)-GN(3)]を得た。ここで用いた14塩基長の場合のアンチセンス核酸GalNAcコンジュゲート体の模式図を図11に示す。高脂血症カニクイザルを用いてHsPCSK9-1811-LNA(14)-GN(3)の薬効確認試験を実施した。なお、GalNAcの結合は、上記の(A)構造のリンカーを介したものであり、下記に示す構造を有する。
HsPCSK9-1811(配列番号14)のLNA架橋構造を有するもの[HsPCSK9-1811-LNA(14)]、及びHsPCSK9-1811(配列番号14)のLNA架橋構造を有しGalNAc修飾を有するもの[HsPCSK9-1811-LNA(14)-GN(3)]の毒性変化を調べるために、6週齢の雄のCrl:CD(SD)ラット(5匹/群)に2週間間歇皮下投与した。HsPCSK9-1811-LNA(14)-GN(3)は試験例6より薬効用量として投与量0.3mg/kgを設定し、その10倍量である3mg/kgを高用量、中間用量として1mg/kgを、またHsPCSK9-1811-LNA(14)は試験例4及び5において腎障害を認めた30mg/kgを設定し、それぞれ週1回、2週間(計2回)投与した。対照群には、生理食塩液を被験物質と同様の方法で皮下に投与した。血液生化学的検査については自動分析装置(JCA-BM6070、日本電子社)により、尿中腎障害分子(Kim-1)はBio-Plex 200(Bio-Rad社)により測定を行った。代表的な結果を図13~16に示す。
GalNAcを結合する主鎖リンカーの構造がアンチセンス核酸の肝臓における活性に与える影響を検証するために、上記の(A)構造又は(B)構造のリンカーを有するアンチセンス核酸GalNAcコンジュゲート体を準備した(それぞれのコンジュゲート体を、A-I体、B-I体と記載する)。Saline(生理食塩水)もしくはアンチセンス核酸GalNAcコンジュゲート体を、8週齢の雄の野生型マウス(日本SLC社)に対して17.5nmol/kgの用量で単回皮下投与を行った。投与3日後に肝臓を摘出し、標的遺伝子発現量をリアルタイムPCRシステム(ABI社)により定量した。なお、GalNAcの具体的な結合構造を下記に示す。
Claims (12)
- 4’位と2’位との間に架橋構造を有する架橋型人工ヌクレオシドを含み、ヒトPCSK9遺伝子と相補的であり、該ヒトPCSK9遺伝子の発現を抑制する活性を有するオリゴヌクレオチドに、アシアロ糖蛋白質受容体に結合し得る分子が直鎖状に2個以上連結して結合してなる、オリゴヌクレオチドコンジュゲート体。
- 架橋構造が下記(i)~(iv)から選ばれる、請求項1記載のオリゴヌクレオチドコンジュゲート体。
(i) -CH2-O-又は-(CH2)2-O-で表される構造
(ii) -CH2-NR1-O-又は-(CH2)2-NR1-O-で表される構造
(iii) -CO-NR1-、-CH2-CO-NR1-、-(CH2)2-CO-NR1-、-CO-NR1-X-又は-CH2-CO-NR1-X-で表される構造
(iv) -CH2-NR1-又は-(CH2)2-NR1-で表される構造
(ここで、R1は、水素原子;
分岐又は環を形成していてもよい炭素数1から7のアルキル基;
分岐又は環を形成していてもよい炭素数2から7のアルケニル基;
水酸基、炭素数1から6の直鎖アルキル基、炭素数1から6の直鎖アルコキシ基、メルカプト基、炭素数1から6の直鎖アルキルチオ基、アミノ基、炭素数1から6の直鎖アルキルアミノ基及びハロゲン原子からなるα群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール基;あるいは
該α群から選択される任意の置換基を1以上有していてもよく、かつ、ヘテロ原子を含んでいてもよい炭素数3から12のアリール部分を有するアルキル基を表し、
Xは、酸素原子、硫黄原子、アミノ基又はメチレン基を表す) - ヒトPCSK9遺伝子が、以下の塩基配列:
配列番号3で示される塩基配列;配列番号4で示される塩基配列;配列番号5で示される塩基配列;配列番号6で示される塩基配列;配列番号7で示される塩基配列;配列番号8で示される塩基配列;配列番号9で示される塩基配列;配列番号10で示される塩基配列;配列番号11で示される塩基配列;配列番号12で示される塩基配列;配列番号13で示される塩基配列;配列番号14で示される塩基配列
又はこれらに相補的な塩基配列のいずれかを含む塩基配列からなる領域である、請求項1又は2記載のオリゴヌクレオチドコンジュゲート体。 - ヌクレオシド間の1又は2以上の結合がホスホロチオエート結合である、請求項1~3いずれか記載のオリゴヌクレオチドコンジュゲート体。
- アシアロ糖蛋白質受容体に結合し得る分子同士の間及びオリゴヌクレオチドとアシアロ糖蛋白質受容体に結合し得る分子との間から選ばれる1又は2以上の結合がホスホジエステル結合である、請求項1~4いずれか記載のオリゴヌクレオチドコンジュゲート体。
- アシアロ糖蛋白質受容体に結合し得る分子の連結個数が2~5である、請求項1~6いずれか記載のオリゴヌクレオチドコンジュゲート体。
- アシアロ糖蛋白質受容体に結合し得る分子が、ラクトース、ガラクトース、N-アセチルガラクトサミン(GalNAc)、ガラクトサミン、N-ホルミルガラクトサミン、N-プロピオニルガラクトサミン、N-n-ブタノイルガラクトサミン、N-イソ-ブタノイルガラクトサミン及びそれらの誘導体からなる群より選ばれる1種又は2種以上である、請求項1~7いずれか記載のオリゴヌクレオチドコンジュゲート体。
- オリゴヌクレオチドの塩基配列の長さが10~25塩基である、請求項1~8いずれか記載のオリゴヌクレオチドコンジュゲート体。
- 請求項1~9いずれか記載のオリゴヌクレオチドコンジュゲート体を有効成分として含有する、LDLコレステロールの高値が関連する疾患の予防又は治療剤。
- LDLコレステロールの高値が関連する疾患が、高コレステロール血症及びLDLコレステロールの低下がより必要である高いリスクを有する疾患から選ばれる、請求項10記載の予防又は治療剤。
- 注射剤である、請求項10又は11記載の予防又は治療剤。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017105121 | 2017-05-26 | ||
JP2017105121 | 2017-05-26 | ||
PCT/JP2018/020081 WO2018216785A1 (ja) | 2017-05-26 | 2018-05-24 | Pcsk9を標的としたアンチセンス核酸 |
JP2019520317A JP6952366B2 (ja) | 2017-05-26 | 2018-05-24 | Pcsk9を標的としたアンチセンス核酸 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019520317A Division JP6952366B2 (ja) | 2017-05-26 | 2018-05-24 | Pcsk9を標的としたアンチセンス核酸 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022017227A true JP2022017227A (ja) | 2022-01-25 |
JP7291418B2 JP7291418B2 (ja) | 2023-06-15 |
Family
ID=64396462
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019520317A Active JP6952366B2 (ja) | 2017-05-26 | 2018-05-24 | Pcsk9を標的としたアンチセンス核酸 |
JP2021154910A Active JP7291418B2 (ja) | 2017-05-26 | 2021-09-22 | Pcsk9を標的としたアンチセンス核酸 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019520317A Active JP6952366B2 (ja) | 2017-05-26 | 2018-05-24 | Pcsk9を標的としたアンチセンス核酸 |
Country Status (4)
Country | Link |
---|---|
US (2) | US11273222B2 (ja) |
EP (1) | EP3633036A4 (ja) |
JP (2) | JP6952366B2 (ja) |
WO (1) | WO2018216785A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JOP20190215A1 (ar) | 2017-03-24 | 2019-09-19 | Ionis Pharmaceuticals Inc | مُعدّلات التعبير الوراثي عن pcsk9 |
US11273222B2 (en) * | 2017-05-26 | 2022-03-15 | National Cerebral And Cardiovascular Center | Antisense nucleic acid targeting PCSK9 |
EP4130266A1 (en) | 2020-03-26 | 2023-02-08 | National Cerebral and Cardiovascular Center | Antisense nucleic acid targeting apoc3 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011505425A (ja) * | 2007-12-04 | 2011-02-24 | アルニラム ファーマスーティカルズ インコーポレイテッド | オリゴヌクレオチドの送達剤としての糖質コンジュゲート |
WO2015179693A1 (en) * | 2014-05-22 | 2015-11-26 | Isis Pharmaceuticals, Inc. | Conjugated antisense compounds and their use |
JP2016526874A (ja) * | 2013-05-01 | 2016-09-08 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | アポリポタンパク質c−iiiの発現を調節するための組成物および方法 |
WO2018216785A1 (ja) * | 2017-05-26 | 2018-11-29 | 国立研究開発法人国立循環器病研究センター | Pcsk9を標的としたアンチセンス核酸 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5731115B2 (ja) | 2006-05-05 | 2015-06-10 | 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 | 遺伝子発現を調節するための化合物および方法 |
US20100216864A1 (en) | 2006-10-09 | 2010-08-26 | Ellen Marie Straarup | RNA Antagonist Compounds for the Modulation of PCSK9 |
US8563528B2 (en) | 2009-07-21 | 2013-10-22 | Santaris Pharma A/S | Antisense oligomers targeting PCSK9 |
CN102596983B (zh) | 2009-10-29 | 2016-06-15 | 国立大学法人大阪大学 | 交联型人工核苷和核苷酸 |
US9127280B2 (en) | 2010-08-31 | 2015-09-08 | Osaka University | Oligonucleotide, and therapeutic agent for dyslipidemia containing oligonucleotide as active ingredient |
CN104837996A (zh) | 2012-11-15 | 2015-08-12 | 罗氏创新中心哥本哈根有限公司 | 抗apob反义缀合物化合物 |
CA2893801A1 (en) | 2013-01-30 | 2014-08-07 | F. Hoffmann-La Roche Ag | Lna oligonucleotide carbohydrate conjugates |
EP3591054A1 (en) | 2013-06-27 | 2020-01-08 | Roche Innovation Center Copenhagen A/S | Antisense oligomers and conjugates targeting pcsk9 |
JOP20190215A1 (ar) * | 2017-03-24 | 2019-09-19 | Ionis Pharmaceuticals Inc | مُعدّلات التعبير الوراثي عن pcsk9 |
-
2018
- 2018-05-24 US US16/616,724 patent/US11273222B2/en active Active
- 2018-05-24 WO PCT/JP2018/020081 patent/WO2018216785A1/ja unknown
- 2018-05-24 EP EP18805466.2A patent/EP3633036A4/en active Pending
- 2018-05-24 JP JP2019520317A patent/JP6952366B2/ja active Active
-
2021
- 2021-09-22 JP JP2021154910A patent/JP7291418B2/ja active Active
-
2022
- 2022-02-03 US US17/649,895 patent/US20220160880A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011505425A (ja) * | 2007-12-04 | 2011-02-24 | アルニラム ファーマスーティカルズ インコーポレイテッド | オリゴヌクレオチドの送達剤としての糖質コンジュゲート |
JP2016526874A (ja) * | 2013-05-01 | 2016-09-08 | アイオーニス ファーマシューティカルズ, インコーポレーテッドIonis Pharmaceuticals,Inc. | アポリポタンパク質c−iiiの発現を調節するための組成物および方法 |
WO2015179693A1 (en) * | 2014-05-22 | 2015-11-26 | Isis Pharmaceuticals, Inc. | Conjugated antisense compounds and their use |
WO2018216785A1 (ja) * | 2017-05-26 | 2018-11-29 | 国立研究開発法人国立循環器病研究センター | Pcsk9を標的としたアンチセンス核酸 |
Non-Patent Citations (1)
Title |
---|
YAMAMOTO, TSUYOSHI ET AL.: "Serial incorporation of a monovalent GalNAc phosphoramidite unit into hepatocyte-targeting antisense", BIOORG. MED. CHEM., vol. 24, JPN6018032671, 2016, pages 26 - 32, ISSN: 0005001094 * |
Also Published As
Publication number | Publication date |
---|---|
WO2018216785A1 (ja) | 2018-11-29 |
EP3633036A4 (en) | 2021-03-17 |
EP3633036A1 (en) | 2020-04-08 |
JP7291418B2 (ja) | 2023-06-15 |
JPWO2018216785A1 (ja) | 2020-03-19 |
JP6952366B2 (ja) | 2021-10-20 |
US11273222B2 (en) | 2022-03-15 |
US20210170032A1 (en) | 2021-06-10 |
US20220160880A1 (en) | 2022-05-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7160807B2 (ja) | 筋ジストロフィーに対するエクソンスキッピングオリゴマーコンジュゲート | |
JP7291418B2 (ja) | Pcsk9を標的としたアンチセンス核酸 | |
JP2024009262A (ja) | Lpaの遺伝子発現の阻害のための組成物及び方法 | |
JP7125940B2 (ja) | 筋ジストロフィーに対するエクソンスキッピングオリゴマーコンジュゲート | |
JP2022103192A (ja) | タウ発現を調節するための組成物 | |
JP6652922B2 (ja) | プレカリクレイン(pkk)発現の調節 | |
KR20190099237A (ko) | 근육 이상증에 대한 엑손 스킵핑 올리고머 결합체 | |
JP2020503070A (ja) | α−1アンチトリプシン(AAT)RNAi剤、AAT RNAi剤を含む組成物、及び使用方法。 | |
KR20160083876A (ko) | ApoB 안티센스 접합체 화합물 | |
BR112015032432B1 (pt) | Oligômero antissenso, conjugados de oligonucleotídeo antissenso, composição farmacêutica, uso dos mesmos para o tratamento da hipercolesterolemia ou distúrbios relacionados e método in vitro para reduzir os níveis de expressão e/ou a atividade de pcsk9 em uma célula | |
JP2018530325A (ja) | アンジオテンシノーゲンの発現を調節するための化合物及び方法 | |
JP2010510807A (ja) | 高コレステロール血症を治療するための方法 | |
EP3687547A1 (en) | Combination therapies for treating muscular dystrophy | |
KR20200057029A (ko) | 근육 이상증에 대한 엑손 스킵핑 올리고머 결합체 | |
JP2021526017A (ja) | 筋ジストロフィーに対するエクソンスキッピングオリゴマーコンジュゲート | |
WO2019067981A1 (en) | POLYTHERAPIES FOR TREATING MUSCLE DYSTROPHY | |
EP3687519A1 (en) | Combination therapies for treating muscular dystrophy | |
CN116669746A (zh) | 一种核酸、含有该核酸的药物组合物与siRNA缀合物及制备方法和用途 | |
WO2014007305A1 (ja) | オリゴヌクレオチド、およびオリゴヌクレオチドを有効成分として含有する脂質異常症治療剤 | |
WO2020033748A1 (en) | Compositions and agents against nonalcoholic steatohepatitis | |
RU2793459C2 (ru) | Композиции и способы модуляции smn2 сплайсинга у субъекта | |
CN117187242A (zh) | 一种siRNA及其缀合物 | |
JP2021521794A (ja) | 筋ジストロフィーに対するエクソンスキッピングオリゴマーおよびオリゴマーコンジュゲート | |
AU2021381363A1 (en) | Compounds and methods for modulating angiotensinogen expression | |
JP2021531009A (ja) | 筋ジストロフィーに対するエクソンスキッピングオリゴマー |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211022 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211022 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220920 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221110 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230228 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230421 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230516 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230529 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7291418 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |