JPWO2020154344A5 - - Google Patents

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JPWO2020154344A5
JPWO2020154344A5 JP2021541717A JP2021541717A JPWO2020154344A5 JP WO2020154344 A5 JPWO2020154344 A5 JP WO2020154344A5 JP 2021541717 A JP2021541717 A JP 2021541717A JP 2021541717 A JP2021541717 A JP 2021541717A JP WO2020154344 A5 JPWO2020154344 A5 JP WO2020154344A5
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nucleotide
oligonucleotide
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Priority claimed from PCT/US2020/014512 external-priority patent/WO2020154344A1/en
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オリゴヌクレオチドであって、構造：
［Ａｍ］－Ｘ１－Ｘ２－Ｘ３－［Ｂｎ］
を含み、式中、Ａ及びＢの各々がヌクレオチドであり、
ｍ及びｎが各々、独立して１～５０の整数であり、
Ｘ１、Ｘ２、及びＸ３が各々、独立してヌクレオチドであり、Ｘ１、Ｘ２、またはＸ３のうち少なくとも１つが、式Ｉ～ＶＩ：
Figure 2020154344000001
のいずれか１つの構造を有し、
式中、Ｎ１が、水素または核酸塩基であり、
Ｒ１２が、水素、ヒドロキシ、フルオロ、ハロゲン、Ｃ１～Ｃ６アルキル、Ｃ１～Ｃ６ヘテロアルキル、またはＣ１～Ｃ６アルコキシであり、
Ｒ１３が、水素またはＣ１～Ｃ６アルキルであり、
Ｘ１、Ｘ２、またはＸ３のうち少なくとも１つが、前記式Ｉ～ＩＶのいずれか１つの構造を有する、前記オリゴヌクレオチド。 An oligonucleotide having the structure:
[A m ]-X 1 -X 2 -X 3 -[B n ]
wherein each of A and B is a nucleotide;
m and n are each independently an integer from 1 to 50;
X 1 , X 2 , and X 3 are each independently a nucleotide, and at least one of X 1 , X 2 , or X 3 is represented by Formulas I-VI:
Figure 2020154344000001
having any one structure of
wherein N 1 is hydrogen or a nucleobase;
R 12 is hydrogen, hydroxy, fluoro, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 1 -C 6 alkoxy;
R 13 is hydrogen or C 1 -C 6 alkyl;
Said oligonucleotide, wherein at least one of X 1 , X 2 , or X 3 has the structure of any one of said Formulas I-IV. ［Ａｍ］及び／または［Ｂｎ］の前記ヌクレオチドの少なくとも８０％が、核酸塩基、糖、及びヌクレオシド間結合を含む、請求項１に記載のオリゴヌクレオチド。 2. The oligonucleotide of claim 1, wherein at least 80% of said nucleotides of [ Am ] and/or [ Bn ] comprise nucleobases, sugars and internucleoside linkages. Ｒ１２が、水素、ハロゲン、Ｃ１～Ｃ６アルキル、またはＣ１～Ｃ６ヘテロアルキルである、請求項１または２に記載のオリゴヌクレオチド。 3. The oligonucleotide of claim 1 or 2, wherein R 12 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl. 前記ハロゲンがフルオロである、請求項１～３のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-3, wherein said halogen is fluoro. Ｒ１２が、水素またはＣ１～Ｃ６アルキルである、請求項１～４のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-4, wherein R 12 is hydrogen or C 1 -C 6 alkyl. Ｒ１２が水素である、請求項１～５のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-5, wherein R12 is hydrogen. Ｘ１、Ｘ２、及びＸ３のうち少なくとも１つが前記式Ｉの構造を有し、Ｎ１が核酸塩基である、請求項１～６のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-6, wherein at least one of X 1 , X 2 and X 3 has the structure of Formula I above and N 1 is a nucleobase. Ｘ１が前記式Ｉの構造を有し、Ｎ１が核酸塩基である、請求項７に記載のオリゴヌクレオチド。 8. The oligonucleotide of claim 7, wherein X1 has the structure of Formula I above and N1 is a nucleobase. Ｘ２が前記式Ｉの構造を有し、Ｎ１が核酸塩基である、請求項７または８に記載のオリゴヌクレオチド。 9. The oligonucleotide of claim 7 or 8, wherein X2 has the structure of formula I above and N1 is a nucleobase. Ｘ１、Ｘ２、及びＸ３のうち少なくとも１つが前記式ＩＩの構造を有し、Ｎ１が核酸塩基である、請求項１～６のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-6, wherein at least one of X 1 , X 2 and X 3 has the structure of Formula II above and N 1 is a nucleobase. Ｘ１が前記式ＩＩの構造を有し、Ｎ１が核酸塩基である、請求項１０に記載のオリゴヌクレオチド。 11. The oligonucleotide of claim 10 , wherein X1 has the structure of formula II above and N1 is a nucleobase. Ｘ２が前記式ＩＩの構造を有し、Ｎ１が核酸塩基である、請求項１０または１１に記載のオリゴヌクレオチド。 12. The oligonucleotide of claim 10 or 11 , wherein X2 has the structure of formula II above and N1 is a nucleobase. Ｘ１、Ｘ２、及びＸ３のうち少なくとも１つが前記式ＩＶの構造を有し、Ｎ１が核酸塩基である、請求項１～６のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-6, wherein at least one of X 1 , X 2 and X 3 has the structure of formula IV above and N 1 is a nucleobase. Ｘ１が前記式ＩＶの構造を有し、Ｎ１が核酸塩基である、請求項１３に記載のオリゴヌクレオチド。 14. The oligonucleotide of claim 13 , wherein X1 has the structure of Formula IV above and N1 is a nucleobase. Ｘ２が前記式ＩＶの構造を有し、Ｎ１が核酸塩基である、請求項１３または１４に記載のオリゴヌクレオチド。 15. The oligonucleotide of claim 13 or 14, wherein X2 has the structure of formula IV above and N1 is a nucleobase. Ｘ１、Ｘ２、及びＸ３のうち少なくとも１つが前記式ＩＩＩの構造を有し、Ｎ１が核酸塩基である、請求項１～６のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-6, wherein at least one of X 1 , X 2 and X 3 has the structure of formula III above and N 1 is a nucleobase. Ｘ１が前記式ＩＩＩの構造を有し、Ｎ１が核酸塩基である、請求項１６に記載のオリゴヌクレオチド。 17. The oligonucleotide of claim 16 , wherein X1 has the structure of Formula III above and N1 is a nucleobase. Ｘ２が前記式ＩＩＩの構造を有し、Ｎ１が核酸塩基である、請求項１６または１７に記載のオリゴヌクレオチド。 18. The oligonucleotide of claim 16 or 17, wherein X2 has the structure of formula III above and N1 is a nucleobase. Ｘ２が前記式Ｉの構造を有しない、請求項１～８及び１０～１８のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-8 and 10-18, wherein X 2 does not have the structure of formula I above. Ｘ３が前記式Ｉの構造を有しない、請求項１～１９のいずれか１項に記載のオリゴヌクレオチド。 20. The oligonucleotide of any one of claims 1-19 , wherein X3 does not have the structure of Formula I above. Ｘ２が前記式ＩＩの構造を有しない、請求項１～１１及び１３～２０のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-11 and 13-20, wherein X 2 does not have the structure of formula II. Ｘ３が前記式ＩＩの構造を有しない、請求項１～２１のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-21, wherein X 3 does not have the structure of formula II. Ｘ２が前記式ＩＶの構造を有しない、請求項１～１４及び１６～２２のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-14 and 16-22, wherein X 2 does not have the structure of formula IV. Ｘ２が前記式Ｉまたは式ＩＩの構造を有する、請求項１～６のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-6, wherein X2 has the structure of Formula I or Formula II . Ｘ１が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ２及びＸ３の各々が、独立してリボヌクレオチド、２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、２’－アミノヌクレオチド、アラビノ核酸ヌクレオチド、二環式ヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、拘束エチルヌクレオチド、ＬＮＡヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ２が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１及びＸ３の各々が、独立してリボヌクレオチド、２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、２’－アミノヌクレオチド、アラビノ核酸ヌクレオチド、二環式ヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、拘束エチルヌクレオチド、ＬＮＡヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ３が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１及びＸ２の各々が、独立してリボヌクレオチド、２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、２’－アミノヌクレオチド、アラビノ核酸ヌクレオチド、二環式ヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、拘束エチルヌクレオチド、ＬＮＡヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ１及びＸ２の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ３が、リボヌクレオチド、２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、２’－アミノヌクレオチド、アラビノ核酸ヌクレオチド、二環式ヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、拘束エチルヌクレオチド、ＬＮＡヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ１及びＸ３の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ２が、リボヌクレオチド、２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、２’－アミノヌクレオチド、アラビノ核酸ヌクレオチド、二環式ヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、拘束エチルヌクレオチド、ＬＮＡヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ２及びＸ３の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１が、リボヌクレオチド、２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、２’－アミノヌクレオチド、アラビノ核酸ヌクレオチド、二環式ヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、拘束エチルヌクレオチド、ＬＮＡヌクレオチド、またはＤＮＡヌクレオチドである、請求項１～２４のいずれか１項に記載のオリゴヌクレオチド。 When X 1 has the structure of any one of Formulas I-VI above, each of X 2 and X 3 is independently a ribonucleotide, 2′-O—C 1 -C 6 alkyl nucleotide, 2′- amino nucleotide, arabinonucleic acid nucleotide, bicyclic nucleotide, 2′-F-nucleotide, 2′-O-methoxyethyl nucleotide, constrained ethyl nucleotide, LNA nucleotide, or DNA nucleotide, and X 2 is each of X 1 and X 3 is independently a ribonucleotide, 2′-O—C 1 -C 6 alkyl nucleotide, 2′-aminonucleotide, arabinonucleotide nucleotide, bicyclic of the formula nucleotide, 2′-F-nucleotide, 2′-O-methoxyethyl nucleotide, constrained ethyl nucleotide, LNA nucleotide, or DNA nucleotide, where X 3 has the structure of any one of formulas I-VI above , X 1 and X 2 are independently ribonucleotides, 2′-O—C 1 -C 6 alkyl nucleotides, 2′-amino nucleotides, arabinonucleotide nucleotides, bicyclic nucleotides, 2′-F-nucleotides , 2′-O-methoxyethyl nucleotides, constrained ethyl nucleotides, LNA nucleotides, or DNA nucleotides, and each of X 1 and X 2 has the structure of any one of Formulas I-VI above, then X 3 is , ribonucleotides, 2′-O—C 1 -C 6 alkyl nucleotides, 2′-aminonucleotides, arabinonucleotides, bicyclic nucleotides, 2′-F-nucleotides, 2′-O-methoxyethyl nucleotides, constrained ethyl When X 1 and X 3 are nucleotides, LNA nucleotides, or DNA nucleotides and each of X 1 and X 3 has the structure of any one of Formulas I-VI above, X 2 is a ribonucleotide, 2′-O—C 1 to C 6 alkyl nucleotide, 2′-amino nucleotide, arabinonucleic acid nucleotide, bicyclic nucleotide, 2′-F-nucleotide, 2′-O-methoxyethyl nucleotide, constrained ethyl nucleotide, LNA nucleotide, or DNA nucleotide, and X 2 and X 3 each have the structure of any one of Formulas I-VI above, X 1 is a ribonucleotide, a 2′-O—C 1 -C 6 alkyl nucleotide, a 2′-amino nucleotide, 25. An arabinonucleotide nucleotide, bicyclic nucleotide, 2'-F-nucleotide, 2'-O-methoxyethyl nucleotide, constrained ethyl nucleotide, LNA nucleotide, or DNA nucleotide, according to any one of claims 1 to 24. of oligonucleotides. Ｘ１が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ２及びＸ３の各々が、独立してリボヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ２が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１及びＸ３の各々が、独立してリボヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ３が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１及びＸ２の各々が、独立してリボヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ１及びＸ２の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ３が、リボヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ１及びＸ３の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ２が、リボヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、またはＤＮＡヌクレオチドであり、Ｘ２及びＸ３の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１が、リボヌクレオチド、２’－Ｆ－ヌクレオチド、２’－Ｏ－メトキシエチルヌクレオチド、またはＤＮＡヌクレオチドである、請求項２５に記載のオリゴヌクレオチド。 When X 1 has the structure of any one of Formulas I-VI above, each of X 2 and X 3 is independently a ribonucleotide, a 2′-F-nucleotide, a 2′-O-methoxyethyl nucleotide, or a DNA nucleotide, and when X 2 has the structure of any one of Formulas I-VI above, each of X 1 and X 3 is independently a ribonucleotide, 2′-F-nucleotide, 2′- O-methoxyethyl nucleotides, or DNA nucleotides, and when X 3 has the structure of any one of Formulas I-VI above, each of X 1 and X 2 is independently a ribonucleotide, 2'-F -nucleotide, 2'-O-methoxyethyl nucleotide, or DNA nucleotide, and each of X 1 and X 2 has the structure of any one of Formulas I-VI above, X 3 is a ribonucleotide, 2 is a '-F-nucleotide, a 2'-O-methoxyethyl nucleotide, or a DNA nucleotide, and each of X 1 and X 3 has the structure of any one of Formulas I-VI above, X 2 is a ribonucleotide; X 1 when it is a nucleotide, a 2′-F-nucleotide, a 2′-O-methoxyethyl nucleotide, or a DNA nucleotide, and each of X 2 and X 3 has the structure of any one of Formulas I-VI above; is a ribonucleotide, a 2'-F-nucleotide, a 2'-O-methoxyethyl nucleotide, or a DNA nucleotide. Ｘ１が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ２及びＸ３の各々がリボヌクレオチドであり、Ｘ２が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１及びＸ３の各々がリボヌクレオチドであり、Ｘ３が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１及びＸ２の各々がリボヌクレオチドであり、Ｘ１及びＸ２の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ３がリボヌクレオチドであり、Ｘ１及びＸ３の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ２がリボヌクレオチドであり、Ｘ２及びＸ３の各々が、前記式Ｉ～ＶＩのいずれか１つの構造を有する場合、Ｘ１がリボヌクレオチドである、請求項２６に記載のオリゴヌクレオチド。 When X 1 has the structure of any one of Formulas I-VI above, When each of X 2 and X 3 is a ribonucleotide, and X 2 has the structure of any one of Formulas I-VI above , X 1 and X 3 is a ribonucleotide, and X 3 has the structure of any one of Formulas I-VI above, then each of X 1 and X 2 is a ribonucleotide, and X 1 and X 2 has the structure of any one of Formulas I-VI above, X 3 is a ribonucleotide, and each of X 1 and X 3 has the structure of any one of Formulas I-VI above. X 2 is a ribonucleotide and X 1 is a ribonucleotide when each of X 2 and X 3 has the structure of any one of said formulas I-VI . Ｘ１がヒポキサンチン核酸塩基を含む、請求項１～２７のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-27, wherein X 1 comprises a hypoxanthine nucleobase. Ｘ１がウラシル核酸塩基を含む、請求項１～２７のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-27, wherein X 1 comprises a uracil nucleobase. Ｘ１がシトシン核酸塩基を含む、請求項１～２７のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-27, wherein X 1 comprises a cytosine nucleobase. Ｘ３がヒポキサンチン核酸塩基を含む、請求項１～３０のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-30 , wherein X3 comprises a hypoxanthine nucleobase. Ｘ３がグアニン核酸塩基を含む、請求項１～３０のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-30 , wherein X3 comprises a guanine nucleobase. Ｘ３がアデニン核酸塩基を含む、請求項１～３０のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-30 , wherein X3 comprises an adenine nucleobase. Ｘ２がシトシン核酸塩基を含む、請求項１～３３のいずれか１項に記載のオリゴヌクレオチド。 34. The oligonucleotide of any one of claims 1-33, wherein X2 comprises a cytosine nucleobase. Ｘ２がウラシル核酸塩基を含む、請求項１～３３のいずれか１項に記載のオリゴヌクレオチド。 34. The oligonucleotide of any one of claims 1-33, wherein X2 comprises a uracil nucleobase. Ｘ２が核酸塩基を含まない、請求項１～３３のいずれか１項に記載のオリゴヌクレオチド。 34. The oligonucleotide of any one of claims 1-33, wherein X2 does not contain a nucleobase. Ｘ２が２’－Ｏ－メチルヌクレオチドではない、請求項１～３６のいずれか１項に記載のオリゴヌクレオチド。 37. The oligonucleotide of any one of claims 1-36, wherein X2 is not a 2'-O-methyl nucleotide. Ｘ１、Ｘ２、及びＸ３が、２’－Ｏ－メチルヌクレオチドではない、請求項１～３７のいずれか１項に記載のオリゴヌクレオチド。 38. The oligonucleotide of any one of claims 1-37, wherein X 1 , X 2 and X 3 are not 2'-O-methyl nucleotides. ［Ａｍ］が、少なくとも１個のヌクレアーゼ耐性ヌクレオチドを含む、請求項１～３８のいずれか１項に記載のオリゴヌクレオチド。 39. The oligonucleotide of any one of claims 1-38, wherein [A m ] comprises at least one nuclease-resistant nucleotide. ［Ａｍ］が、少なくとも１個の２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、少なくとも１個の２’－アミノヌクレオチド、少なくとも１個のアラビノ核酸ヌクレオチド、少なくとも１個の二環式ヌクレオチド、少なくとも１個の２’－Ｆ－ヌクレオチド、少なくとも１個の２’－Ｏ－メトキシエチルヌクレオチド、少なくとも１個の拘束エチル（ｃＥｔ）ヌクレオチド、少なくとも１個のＬＮＡヌクレオチド、及び／または少なくとも１個のＤＮＡヌクレオチドを含む、請求項１～３９のいずれか１項に記載のオリゴヌクレオチド。 [A m ] is at least one 2′-O—C 1 -C 6 alkyl nucleotide, at least one 2′-amino nucleotide, at least one arabinonucleic acid nucleotide, at least one bicyclic nucleotide; at least one 2'-F-nucleotide, at least one 2'-O-methoxyethyl nucleotide, at least one constrained ethyl (cEt) nucleotide, at least one LNA nucleotide, and/or at least one DNA 40. The oligonucleotide of any one of claims 1-39, comprising nucleotides. ［Ａｍ］が、少なくとも１個の２’－Ｏ－メチルヌクレオチド、少なくとも１個の２’－Ｆ－ヌクレオチド、少なくとも１個の２’－Ｏ－メトキシエチルヌクレオチド、少なくとも１個のｃＥｔヌクレオチド、少なくとも１個のＬＮＡヌクレオチド、及び／または少なくとも１個のＤＮＡヌクレオチドを含む、請求項４０に記載のオリゴヌクレオチド。 [A m ] is at least one 2′-O-methyl nucleotide, at least one 2′-F-nucleotide, at least one 2′-O-methoxyethyl nucleotide, at least one cEt nucleotide, at least 41. Oligonucleotide according to claim 40, comprising one LNA nucleotide and/or at least one DNA nucleotide. ［Ａｍ］が、少なくとも５個の末端２’－Ｏ－メチルヌクレオチドを含む、請求項１～４１のいずれか１項に記載のオリゴヌクレオチド。 42. The oligonucleotide of any one of claims 1-41, wherein [A m ] comprises at least five terminal 2'-O-methyl nucleotides. ［Ａｍ］が、少なくとも１つのホスホロチオエート結合を含む、請求項１～４２のいずれか１項に記載のオリゴヌクレオチド。 43. The oligonucleotide of any one of claims 1-42, wherein [A m ] comprises at least one phosphorothioate linkage. ［Ａｍ］が、少なくとも４つの末端ホスホロチオエート結合を含む、請求項１～４３のいずれか１項に記載のオリゴヌクレオチド。 44. The oligonucleotide of any one of claims 1-43, wherein [A m ] comprises at least four terminal phosphorothioate linkages. 少なくとも１つのホスホロチオエート結合が立体的に純粋である、請求項４３または４４に記載のオリゴヌクレオチド。 45. The oligonucleotide of claim 43 or 44, wherein at least one phosphorothioate linkage is sterically pure. ［Ｂｎ］が、少なくとも１個のヌクレアーゼ耐性ヌクレオチドを含む、請求項１～４５のいずれか１項に記載のオリゴヌクレオチド。 46. The oligonucleotide of any one of claims 1-45, wherein [B n ] comprises at least one nuclease-resistant nucleotide. ［Ｂｎ］が、少なくとも１個の２’－Ｏ－Ｃ１～Ｃ６アルキルヌクレオチド、少なくとも１個の２’－アミノヌクレオチド、少なくとも１個のアラビノ核酸ヌクレオチド、少なくとも１個の二環式ヌクレオチド、少なくとも１個の２’－Ｆ－ヌクレオチド、少なくとも１個の２’－Ｏ－メトキシエチルヌクレオチド、少なくとも１個のｃＥｔヌクレオチド、少なくとも１個のＬＮＡヌクレオチド、及び／または少なくとも１個のＤＮＡヌクレオチドを含む、請求項１～４６のいずれか１項に記載のオリゴヌクレオチド。 [B n ] is at least one 2′-O—C 1 -C 6 alkyl nucleotide, at least one 2′-amino nucleotide, at least one arabinonucleic acid nucleotide, at least one bicyclic nucleotide; at least one 2'-F-nucleotide, at least one 2'-O-methoxyethyl nucleotide, at least one cEt nucleotide, at least one LNA nucleotide, and/or at least one DNA nucleotide; An oligonucleotide according to any one of claims 1-46. ［Ｂｎ］が、少なくとも１個の２’－Ｏ－メチルヌクレオチド、少なくとも１個の２’－Ｆ－ヌクレオチド、少なくとも１個の２’－Ｏ－メトキシエチルヌクレオチド、少なくとも１個のｃＥｔヌクレオチド、少なくとも１個のＬＮＡヌクレオチド、及び／または少なくとも１個のＤＮＡヌクレオチドを含む、請求項４７に記載のオリゴヌクレオチド。 [B n ] is at least one 2′-O-methyl nucleotide, at least one 2′-F-nucleotide, at least one 2′-O-methoxyethyl nucleotide, at least one cEt nucleotide, at least 48. Oligonucleotide according to claim 47, comprising one LNA nucleotide and/or at least one DNA nucleotide. ［Ｂｎ］が、少なくとも５個の末端２’－Ｏ－メチルヌクレオチドを含む、請求項１～４８のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-48, wherein [B n ] comprises at least 5 terminal 2'-O-methyl nucleotides. ［Ｂｎ］が、少なくとも１つのホスホロチオエート結合を含む、請求項１～４９のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-49, wherein [B n ] comprises at least one phosphorothioate linkage. ［Ｂｎ］が、少なくとも４つの末端ホスホロチオエート結合を含む、請求項１～５０のいずれか１項に記載のオリゴヌクレオチド。 51. The oligonucleotide of any one of claims 1-50, wherein [B n ] comprises at least four terminal phosphorothioate linkages. 少なくとも１つのホスホロチオエート結合が立体的に純粋である、請求項５０または請求項５１に記載のオリゴヌクレオチド。 52. The oligonucleotide of claim 50 or claim 51, wherein at least one phosphorothioate linkage is sterically pure. ［Ａｍ］及び［Ｂｎ］の全て合わせた前記ヌクレオチドの少なくとも２０％が２’－Ｏ－メチルヌクレオチドである、請求項１～５２のいずれか１項に記載のオリゴヌクレオチド。 53. The oligonucleotide of any one of claims 1-52, wherein at least 20% of said nucleotides combined of all [A m ] and [B n ] are 2'-O-methyl nucleotides. 前記オリゴヌクレオチドが、さらに５’キャップ構造を含む、請求項１～５３のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-53, wherein said oligonucleotide further comprises a 5' cap structure. 前記オリゴヌクレオチドが、少なくとも１個の代替核酸塩基を含む、請求項１～５４のいずれか１項に記載のオリゴヌクレオチド。 The oligonucleotide of any one of claims 1-54, wherein said oligonucleotide comprises at least one alternative nucleobase. ５’末端ヌクレオチドが２’－アミノヌクレオチドである、請求項１～５５のいずれか１項に記載のオリゴヌクレオチド。 56. The oligonucleotide of any one of claims 1-55, wherein the 5 ' terminal nucleotide is a 2'-aminonucleotide. 全て合わせたＡ及びＢが、１８～８０個のヌクレオチドからなる、請求項１～５６のいずれか１項に記載のオリゴヌクレオチド。 57. The oligonucleotide of any one of claims 1-56, wherein A and B taken together consist of 18-80 nucleotides. ｍが５～４０である、請求項１～５７のいずれか１項に記載のオリゴヌクレオチド。 58. The oligonucleotide of any one of claims 1-57, wherein m is 5-40. ｎが５～４０である、請求項１～５８のいずれか１項に記載のオリゴヌクレオチド。 59. The oligonucleotide of any one of claims 1-58, wherein n is 5-40. ｍ及びｎが各々、独立して５～４０の整数であり、Ｘ１、Ｘ２、及びＸ３のうち少なくとも１つが、前記式Ｉ、式ＩＩ、式ＩＩＩ、または式ＩＶの構造を有し、式中、Ｎ１が核酸塩基であり、前記式Ｉ、式ＩＩ、式ＩＩＩ、または式ＩＶの構造を有しないＸ１、Ｘ２、及びＸ３の各々が、リボヌクレオチドであり、［Ａｍ］及び［Ｂｎ］が各々、少なくとも５個の末端２’－Ｏ－メチルヌクレオチド及び少なくとも４つの末端ホスホロチオエート結合を含み、［Ａｍ］及び［Ｂｎ］の全て合わせた前記ヌクレオチドの少なくとも２０％が２’－Ｏ－メチルヌクレオチドである、請求項１に記載のオリゴヌクレオチド。 m and n are each independently an integer from 5 to 40, and at least one of X 1 , X 2 , and X 3 has the structure of Formula I, Formula II, Formula III, or Formula IV above; , wherein N 1 is a nucleobase and each of X 1 , X 2 , and X 3 not having the structure of Formula I, Formula II, Formula III, or Formula IV is a ribonucleotide, [A m ] and [B n ] each contain at least 5 terminal 2′-O-methyl nucleotides and at least 4 terminal phosphorothioate linkages, and at least 20 of said nucleotides of [A m ] and [B n ] taken together. The oligonucleotide of claim 1, wherein % are 2'-O-methyl nucleotides. 前記オリゴヌクレオチドが、１つ以上のＲＮＡに作用するアデノシンデアミナーゼ（ＡＤＡＲ）動員ドメインをさらに含む、請求項１～６０のいずれか１項に記載のオリゴヌクレオチド。 61. The oligonucleotide of any one of claims 1-60, wherein said oligonucleotide further comprises one or more RNA-acting adenosine deaminase (ADAR) recruitment domains. 標的化部分に複合化された、請求項１～６１のいずれか１項に記載のオリゴヌクレオチドを含む、複合体。 A conjugate comprising the oligonucleotide of any one of claims 1-61 conjugated to a targeting moiety. 前記標的化部分が、脂質、ステロール、炭水化物、及び／またはペプチドである、請求項６２に記載の複合体。 63. The conjugate of claim 62 , wherein said targeting moiety is a lipid, sterol, carbohydrate and/or peptide. 複合物であって、
請求項１～６１のいずれか１項に記載のオリゴヌクレオチドまたは請求項６２もしくは６３に記載の複合体と、
ｍＲＮＡとを含み、
前記オリゴヌクレオチドまたは前記複合体及び前記ｍＲＮＡが互いにハイブリダイズされ、前記複合物が、前記ｍＲＮＡのアデノシンに第１ミスマッチを含む、前記複合物。 a compound,
The oligonucleotide according to any one of claims 1 to 61 or the complex according to claim 62 or 63,
mRNA and
Said oligonucleotide or said complex and said mRNA are hybridized to each other, said composite comprising a first mismatch at an adenosine of said mRNA. 前記複合物が、前記第１ミスマッチの５’側に４個のヌクレオチドである第２ミスマッチを含む、請求項６４に記載の複合物。 65. The composite of Claim 64, wherein said composite comprises a second mismatch that is 4 nucleotides 5' to said first mismatch. 前記複合物が、１つ、２つ、３つ、４つ、５つ、６つ、７つ、または８つのミスマッチを含む、請求項６４または６５に記載の複合物。 66. The composite of claims 64 or 65, wherein the composite contains 1, 2, 3, 4, 5, 6, 7, or 8 mismatches. 前記ｍＲＮＡが、治療結果をもたらすために脱アミノ化される可能性のあるアデノシンを含む、請求項６４～６６のいずれか１項に記載の複合物。 The conjugate of any one of claims 64-66, wherein said mRNA comprises adenosine, which may be deaminated to provide therapeutic results. 前記ｍＲＮＡが、対応する天然ｍＲＮＡと比較して、グアノシンからアデノシンへの変異を含む、請求項６４～６６のいずれか１項に記載の複合物。 The composite of any one of claims 64-66, wherein said mRNA comprises a guanosine to adenosine mutation compared to the corresponding native mRNA. 前記グアノシンからアデノシンへの変異が、ミスセンス変異またはナンセンス変異である、請求項６８に記載の複合物。 69. The compound of claim 68, wherein said guanosine to adenosine mutation is a missense or nonsense mutation. 前記第１ミスマッチが、前記ｍＲＮＡの開始コドン中のアデノシンにある、請求項６４～６９のいずれか１項に記載の複合物。 The compound of any one of claims 64-69, wherein said first mismatch is at an adenosine in the start codon of said mRNA. 前記第１ミスマッチが、前記ｍＲＮＡの終止コドン中のアデノシンにある、請求項６４～６９のいずれか１項に記載の複合物。 The compound of any one of claims 64-69, wherein said first mismatch is at an adenosine in the stop codon of said mRNA. 前記終止コドンが未成熟終止コドンである、請求項７１に記載の複合物。 72. The compound of claim 71, wherein said stop codon is a premature stop codon. 請求項６４～７２のいずれか１項に記載の複合物の作製方法であって、細胞を請求項１～６１のいずれか１項に記載のオリゴヌクレオチドまたは請求項６２もしくは６３に記載の複合体と接触させることを含む、前記方法。 A method for producing a conjugate according to any one of claims 64 to 72, wherein a cell is an oligonucleotide according to any one of claims 1 to 61 or a conjugate according to claim 62 or The method, comprising contacting with ｍＲＮＡ中のアデノシンの脱アミノ化方法であって、細胞を請求項１～６１のいずれか１項に記載のオリゴヌクレオチドまたは請求項６２もしくは６３に記載の複合体と接触させることを含む、前記方法。 64. A method for deamination of adenosine in mRNA comprising contacting a cell with an oligonucleotide according to any one of claims 1-61 or a conjugate according to claims 62 or 63. . 障害の処置を必要とする対象の障害を処置するための医薬であって、有効量の請求項１～６１のいずれか１項に記載のオリゴヌクレオチドまたは請求項６２もしくは６３に記載の複合体を含む、医薬。 A medicament for treating a disorder in a subject in need thereof, comprising an effective amount of the oligonucleotide of any one of claims 1-61 or the conjugate of claim 62 or 63. Including , medicine . 前記障害が、嚢胞性線維症、白皮症、アルファ－１－アンチトリプシン欠損症、アルツハイマー病、筋萎縮性側索硬化症、喘息、１１サラセミア、Ｃａｄａｓｉｌ症候群、シャルコー・マリー・トゥース病、慢性閉塞性肺疾患、遠位型脊髄性筋萎縮症、デュシェンヌ型／ベッカー型筋ジストロフィー、栄養障害型表皮水疱症、表皮水疱症、ファブリー病、第Ｖ因子ライデン関連障害、家族性大腸腺腫症、ガラクトース血症、ゴーシェ病、グルコース－６－リン酸デヒドロゲナーゼ欠損症、血友病、遺伝性ヘモクロマトーシス、ハンター症候群、ハンチントン病、ハーラー症候群、炎症性腸疾患、遺伝性多凝集症候群、レーバー先天性黒内障、レッシュ・ナイハン症候群、リンチ症候群、マルファン症候群、ムコ多糖症、筋ジストロフィー、筋強直性ジストロフィーＩ型及びＩＩ型、神経線維腫、ニーマン・ピック病Ａ型、Ｂ型及びＣ型、ＮＹ－ＥＳＯ－１関連がん、パーキンソン病、ポイツ・ジェガース症候群、フェニルケトン尿症、ポンペ病、原発性線毛疾患、プロトロンビン変異関連障害、肺高血圧症、網膜色素変性症、サンドホフ病、重症複合免疫不全症候群、鎌状赤血球貧血、脊髄性筋萎縮症、シュタルガルト病、テイ・サックス病、アッシャー症候群、Ｘ連鎖性免疫不全、スタージ・ウェーバー症候群、レット症候群、またはがんである、請求項７５に記載の医薬。 The disorder is cystic fibrosis, albinism, alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, asthma, thalassemia 11, Cadasil syndrome, Charcot-Marie-Tooth disease, chronic obstruction pulmonary disease, distal spinal muscular atrophy, Duchenne/Becker muscular dystrophy, dystrophic epidermolysis bullosa, epidermolysis bullosa, Fabry disease, factor V Leiden-related disorders, familial adenomatous polyposis, galactosemia , Gaucher disease, glucose-6-phosphate dehydrogenase deficiency, hemophilia, hereditary hemochromatosis, Hunter's syndrome, Huntington's disease, Hurler's syndrome, inflammatory bowel disease, hereditary polyagglutination syndrome, Leber congenital amaurosis, Lesch・Nyhan syndrome, Lynch syndrome, Marfan syndrome, mucopolysaccharidosis, muscular dystrophy, myotonic dystrophy type I and II, neurofibroma, Niemann-Pick disease type A, B and C, NY-ESO-1 related Cancer, Parkinson's disease, Peutz-Jeghers syndrome, phenylketonuria, Pompe disease, primary ciliary disease, prothrombin mutation-related disorder, pulmonary hypertension, retinitis pigmentosa, Sandhoff disease, severe combined immunodeficiency syndrome, sickle 76. The medicament of claim 75, which is erythrocytic anemia, spinal muscular atrophy, Stargardt disease, Tay-Sachs disease, Usher syndrome, X-linked immunodeficiency, Sturge-Weber syndrome, Rett syndrome, or cancer.
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