KR102339196B1 - 펩타이드 올리고뉴클레오타이드 접합체 - Google Patents
펩타이드 올리고뉴클레오타이드 접합체 Download PDFInfo
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- KR102339196B1 KR102339196B1 KR1020217007616A KR20217007616A KR102339196B1 KR 102339196 B1 KR102339196 B1 KR 102339196B1 KR 1020217007616 A KR1020217007616 A KR 1020217007616A KR 20217007616 A KR20217007616 A KR 20217007616A KR 102339196 B1 KR102339196 B1 KR 102339196B1
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- Prior art keywords
- conjugate
- delete delete
- alkyl
- carrier peptide
- oligomer
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 164
- 108091034117 Oligonucleotide Proteins 0.000 title abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- -1 4-methoxytrityl Chemical group 0.000 claims description 138
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 132
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 229940024606 amino acid Drugs 0.000 claims description 97
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 83
- 150000001413 amino acids Chemical class 0.000 claims description 82
- 229960002684 aminocaproic acid Drugs 0.000 claims description 76
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 76
- 150000007523 nucleic acids Chemical class 0.000 claims description 74
- 102000039446 nucleic acids Human genes 0.000 claims description 72
- 108020004707 nucleic acids Proteins 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 229940000635 beta-alanine Drugs 0.000 claims description 31
- 239000004475 Arginine Substances 0.000 claims description 25
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 25
- 125000003729 nucleotide group Chemical group 0.000 claims description 20
- 239000002773 nucleotide Substances 0.000 claims description 19
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 18
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 16
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 15
- 210000004899 c-terminal region Anatomy 0.000 claims description 14
- 125000003696 stearoyl 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])([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 claims description 13
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 8
- 229940035893 uracil Drugs 0.000 claims description 8
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 229940104302 cytosine Drugs 0.000 claims description 6
- 229930010555 Inosine Natural products 0.000 claims description 5
- 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 claims description 5
- 229960003786 inosine Drugs 0.000 claims description 5
- 229930024421 Adenine Natural products 0.000 claims description 4
- 229960000643 adenine Drugs 0.000 claims description 4
- 230000009870 specific binding Effects 0.000 claims description 4
- 229940113082 thymine Drugs 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 abstract description 51
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- 238000012986 modification Methods 0.000 abstract description 28
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- 230000002159 abnormal effect Effects 0.000 abstract 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 264
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
- 239000000562 conjugate Substances 0.000 description 156
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 description 139
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 description 139
- 239000004471 Glycine Substances 0.000 description 137
- 230000000692 anti-sense effect Effects 0.000 description 132
- 235000013930 proline Nutrition 0.000 description 129
- 108010068380 arginylarginine Proteins 0.000 description 126
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 117
- 239000002585 base Substances 0.000 description 96
- 235000001014 amino acid Nutrition 0.000 description 92
- OMLWNBVRVJYMBQ-YUMQZZPRSA-N Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O OMLWNBVRVJYMBQ-YUMQZZPRSA-N 0.000 description 90
- 229910052739 hydrogen Inorganic materials 0.000 description 81
- 239000001257 hydrogen Substances 0.000 description 79
- 239000000243 solution Substances 0.000 description 67
- 108020004414 DNA Proteins 0.000 description 61
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 55
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- 239000011347 resin Substances 0.000 description 49
- 229920005989 resin Polymers 0.000 description 49
- 125000000623 heterocyclic group Chemical group 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 44
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 40
- 125000003118 aryl group Chemical group 0.000 description 38
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 37
- 230000000295 complement effect Effects 0.000 description 37
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000000203 mixture Substances 0.000 description 34
- 235000018102 proteins Nutrition 0.000 description 34
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 33
- 230000027455 binding Effects 0.000 description 33
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
- 125000005647 linker group Chemical group 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 28
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 28
- 150000003254 radicals Chemical class 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- 230000000694 effects Effects 0.000 description 27
- 235000009697 arginine Nutrition 0.000 description 26
- 230000003612 virological effect Effects 0.000 description 25
- QVVDVENEPNODSI-BTNSXGMBSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylidene Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QVVDVENEPNODSI-BTNSXGMBSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 23
- 125000001072 heteroaryl group Chemical group 0.000 description 23
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 125000004103 aminoalkyl group Chemical group 0.000 description 21
- 125000003710 aryl alkyl group Chemical group 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
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- 230000001965 increasing effect Effects 0.000 description 20
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 description 19
- 125000002947 alkylene group Chemical group 0.000 description 19
- 230000008685 targeting Effects 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- 102000004196 processed proteins & peptides Human genes 0.000 description 18
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- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
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- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 15
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- 230000002401 inhibitory effect Effects 0.000 description 15
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- 231100000419 toxicity Toxicity 0.000 description 15
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US13/101,942 US20110269665A1 (en) | 2009-06-26 | 2011-05-05 | Compound and method for treating myotonic dystrophy |
US13/107,528 US9238042B2 (en) | 2010-05-13 | 2011-05-13 | Antisense modulation of interleukins 17 and 23 signaling |
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PCT/US2011/061282 WO2012150960A1 (en) | 2011-05-05 | 2011-11-17 | Peptide oligonucleotide conjugates |
KR1020197019623A KR102229650B1 (ko) | 2011-05-05 | 2011-11-17 | 펩타이드 올리고뉴클레오타이드 접합체 |
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2019
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2020
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2021
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2023
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Patent Citations (1)
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WO2009144481A2 (en) | 2008-05-30 | 2009-12-03 | Isis Innovation Limited | Conjugates for delivery of biologically active compounds |
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JP2018135396A (ja) | 2018-08-30 |
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AU2011367230A1 (en) | 2013-12-05 |
AU2019204913A1 (en) | 2019-07-25 |
KR102183273B1 (ko) | 2020-11-27 |
AU2023203112A1 (en) | 2023-06-08 |
JP6884250B2 (ja) | 2021-06-09 |
AU2017206179A1 (en) | 2017-08-03 |
CA2834128A1 (en) | 2012-11-08 |
KR20140028058A (ko) | 2014-03-07 |
CN103619356A (zh) | 2014-03-05 |
JP2021113232A (ja) | 2021-08-05 |
KR102229650B1 (ko) | 2021-03-19 |
CN107693797B (zh) | 2021-05-11 |
JP2016185991A (ja) | 2016-10-27 |
KR20210032545A (ko) | 2021-03-24 |
AU2023203112B2 (en) | 2025-06-05 |
IL229227B (en) | 2020-07-30 |
CN103619356B (zh) | 2017-09-12 |
WO2012150960A1 (en) | 2012-11-08 |
KR20190084351A (ko) | 2019-07-16 |
IL229227A0 (en) | 2014-01-30 |
CA3092114A1 (en) | 2012-11-08 |
JP6478632B2 (ja) | 2019-03-06 |
CN107693797A (zh) | 2018-02-16 |
JP2024032974A (ja) | 2024-03-12 |
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