Oligonucleotide Compositions and Related Methods - Patent application

Abstract

The present disclosure features useful oligonucleotide compositions and methods related thereto.The present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., sugar modifications, bases and / or internucleotide linkages) or patterns thereof, can have significant effects on oligonucleotide properties and activity.The present disclosure also provides a method for treating disorders in which deamination of adenosine in mRNA, for example, results in therapeutic outcomes in subjects in need thereof.

Claims

1. An oligonucleotide comprising: １ N ０ N －１ -3', N －１ , N ０ and N １ each is independently a nucleoside; (a) N ０ is a nucleobase, 【Chemistry 1】 or BA comprises a ring BA or a tautomer thereof, wherein ring BA is of formula BA-III-e: 【Chemistry 2】 (In the formula, X １ is -N(-)- or -C(-)=, W Ｘ２ and W Ｘ６ each is independently O, S or Se; R Ｂ４ is halogen, -CN, -NO ２ Or -L Ｂ４ -R Ｂ４１ and R Ｂ４１ is R′, R Ｂ５ is halogen, -CN, -NO ２ Or -L Ｂ５ -R Ｂ５１ and R Ｂ５１ is -R', -N(R') ２ , -OR' or -SR', L Ｂ４ and L Ｂ５ Each of the groups independently represents L Ｂ and Each L Ｂ are independently a covalent bond or an optionally substituted divalent C １～１０ is a saturated or partially unsaturated chain, wherein one or more of the methylene units are optionally and independently -Cy-, -O-, -S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ is replaced by -N(R')-, -C(O)S- or -C(O)O-; each -Cy- is independently an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, -C(O)N(R), ２ Or -SO ２ R, and Each R is independently -H or C １～２０ Aliphatic, C with 1-10 heteroatoms １～２０ Heteroaliphatic, C ６～２０ Aryl, C ６～２０ Arylaliphatic, C with 1-10 heteroatoms ６～２０ an optionally substituted group selected from arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms, and 3-20 membered heterocyclyl having 1-10 heteroatoms; or two R groups optionally and independently combine to form a covalent bond, or two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said atom; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said intervening atoms; and (b) N ０ The sugar of formula (I) contains a 2'-OR modification, where R is an optionally substituted C １～６ An oligonucleotide that is aliphatic.

2. N ０ The nucleobase is 【Chemistry 3】 The oligonucleotide of claim 1 ,

3. N ０ The nucleobase is 【Chemistry 4】 The oligonucleotide of claim 1 ,

4. N ０ The nucleobase is 【Chemistry 5】 The oligonucleotide of claim 1 ,

5. N ０ The nucleobase is 【Chemistry 6】 The oligonucleotide of claim 1 ,

6. R Ｂ４ The oligonucleotide of claim 1, wherein:

7. N ０ 3. The oligonucleotide of claim 2, wherein the sugar is a 2'-OMe modified sugar.

8. N ０ 3. The oligonucleotide of claim 2, wherein the sugar is a 2'-MOE modified sugar.

9. 2. The oligonucleotide of claim 1, comprising one or more 2'-F modified sugars.

10. When the oligonucleotide is contacted in a system with a target nucleic acid that contains a target adenosine, the target adenosine in the target nucleic acid is modified and when the oligonucleotide is aligned with the target nucleic acid, N ０ is opposite the target adenosine.

11. 11. The oligonucleotide of claim 10, wherein the target adenosine is a G to A mutation.

12. About 10 to 200 (e.g., about 10 to 20, 10 to 30, 10 to 40, 10 to 50, 10 to 60, 10 to 70, 10 to 80, 10 to 90, 10 to 100, 10 to 120, 10 to 150, 20 to 30, 20 to 40, 20 to 50, 20 to 60, 20 to 70, 20 to 80, 20 to 90, 20 to 100, 20 to 120, 20 to 150, 20 to 200, 25 to 30, 25 to 40, 25 to 50, 25 to 60, 25 to 70, 25 to 80, 25 2. The oligonucleotide of claim 1, having a length of nucleobases of 10, 25 ...

13. The oligonucleotide according to claim 12, wherein the base sequence of the oligonucleotide is complementary to a part of the base sequence of the target nucleic acid containing the target adenosine with 0 to 10 (e.g., 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 0 to 10, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mismatches that are not Watson-Crick base pairs.

14. The complementarity may be from about 50% to 100% (e.g., from about 50% to 80%, 50% to 85%, 50% to 90%, 50% to 95%, 60% to 80%, 60% to 85%, 60% to 90%, 60% to 95%, 60% to 100%, 65% to 80%, 65% to 85%, 65% to 90%, 65% to 95%, 65% to 100%, 70% to 80%, 70% to 85%, 70% to 90%, 70% to 95%, 70% to 100%, 75 ...

14. The oligonucleotide of claim 13, wherein the oligonucleotide is selected from the group consisting of 50% to 80%, 75% to 85%, 75% to 90%, 75% to 95%, 75% to 100%, 80% to 85%, 80% to 90%, 80% to 95%, 80% to 100%, 85% to 90%, 85% to 95%, 85% to 100%, 90% to 95%, 90% to 100%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

15. 15. The oligonucleotide of claim 13 or 14, wherein the complementarity is 100% except for the nucleoside opposite the target adenosine.

16. N －１ 16. The oligonucleotide of any one of claims 1 to 15, wherein the nucleobase is BA, wherein BA comprises a ring BA or a tautomer thereof, and wherein ring BA has the structure of formula BA-III-e:

17. N －１ wherein the nucleobase is BA, 【Chemistry 7】 The oligonucleotide according to any one of claims 1 to 16,

18. a first domain which is an oligonucleotide and has a length of about 2 to 50 nucleobases (e.g., about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50, etc.); and a second domain having a length of about 2 to 50 (e.g., about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50, etc.) nucleobases.

19. An oligonucleotide comprising: １ N ０ N －１ -3', N －１ , N ０ and N １ Each of N is independently a nucleoside; ０ is a nucleobase BA, BA comprising a ring BA or a tautomer thereof, wherein ring BA is represented by the formula BA-III-e: 【Chemistry 8】 (In the formula, X １ is -N(-)- or -C(-)=, W Ｘ２ and W Ｘ６ each is independently O, S or Se; R Ｂ４ is halogen, -CN, -NO ２ Or -L Ｂ４ -R Ｂ４１ and R Ｂ４１ is R′, R Ｂ５ is halogen, -CN, -NO ２ Or -L Ｂ５ -R Ｂ５１ and R Ｂ５１ is -R', -N(R') ２ , -OR' or -SR', L Ｂ４ and L Ｂ５ Each of the groups independently represents L Ｂ and Each L Ｂ are independently a covalent bond or an optionally substituted divalent C １～１０ is a saturated or partially unsaturated chain, wherein one or more of the methylene units are optionally and independently -Cy-, -O-, -S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ is replaced by -N(R')-, -C(O)S- or -C(O)O-; each -Cy- is independently an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, -C(O)N(R), ２ Or -SO ２ R, and Each R is independently -H or C １～２０ Aliphatic, C with 1-10 heteroatoms １～２０ Heteroaliphatic, C ６～２０ Aryl, C ６～２０ Arylaliphatic, C with 1-10 heteroatoms ６～２０ an optionally substituted group selected from arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms, and 3-20 membered heterocyclyl having 1-10 heteroatoms; or two R groups optionally and independently combine to form a covalent bond, or two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said atom; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said intervening atoms; An oligonucleotide having the structure:

20. An oligonucleotide comprising nucleoside N ０ Including N ０ is a nucleobase BA, BA comprising a ring BA or a tautomer thereof, wherein ring BA is represented by the formula BA-III-e: 【Chemistry 9】 (In the formula, X １ is -N(-)- or -C(-)=, W Ｘ２ and W Ｘ６ each is independently O, S or Se; R Ｂ４ is halogen, -CN, -NO ２ Or -L Ｂ４ -R Ｂ４１ and R Ｂ４１ is R′, R Ｂ５ is halogen, -CN, -NO ２ Or -L Ｂ５ -R Ｂ５１ and R Ｂ５１ is -R', -N(R') ２ , -OR' or -SR', L Ｂ４ and L Ｂ５ Each of the groups independently represents L Ｂ and Each L Ｂ are independently a covalent bond or an optionally substituted divalent C １～１０ is a saturated or partially unsaturated chain, wherein one or more of the methylene units are optionally and independently -Cy-, -O-, -S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ is replaced by -N(R')-, -C(O)S- or -C(O)O-; each -Cy- is independently an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, -C(O)N(R), ２ Or -SO ２ R, and Each R is independently -H or C １～２０ Aliphatic, C with 1-10 heteroatoms １～２０ Heteroaliphatic, C ６～２０ Aryl, C ６～２０ Arylaliphatic, C with 1-10 heteroatoms ６～２０ an optionally substituted group selected from arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms, and 3-20 membered heterocyclyl having 1-10 heteroatoms; or two R groups optionally and independently combine to form a covalent bond, or two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said atom; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said intervening atoms; An oligonucleotide having the structure:

21. When the oligonucleotide is aligned with the target nucleic acid, N ０ is opposite the target adenosine.

22. An oligonucleotide comprising: １ N ０ N －１ -3', N －１ , N ０ and N １ Each of N is independently a nucleoside; ０ is a nucleobase BA, wherein BA comprises a ring BA or a tautomer thereof, and ring BA is represented by formula BA-VI: 【Chemistry 10】 (In the formula, each 【Chemistry 11】 is independently a single bond or a double bond; X １’ is -N(-)- or -C(-)=, X ２’ is -C(W Ｘ２’ ) -, -C(R Ｂ２’ ) =, -C(OR Ｂ２’ )=, -N= or optionally substituted -CH= or -CH ２ - and R Ｂ２’ is halogen, -CN, -NO ２ Or -L Ｂ２’ -R' and W Ｘ２’ is O, S or Se, X ３’ is -N(R Ｂ３’ )=, -N=, -C(R Ｂ３’ )= or optionally substituted —NH— or —CH=; R Ｂ３’ is halogen, -CN, -NO ２ Or -L Ｂ３’ -R', X ４’ is -C(R Ｂ４’ ) =, -C(OR Ｂ４’ )=, -C(-N(R Ｂ４’ ) ２ ) = , -C(R Ｂ４’ ) ２ -, -C(W Ｘ４’ ) -, -C(=NR Ｂ４’ ) -, -N(R Ｂ４’ )-, -N=, or optionally substituted -CH=, -NH-, or -CH ２ -, and each R Ｂ４’ are independently halogen, -CN, -NO ２ Or -L Ｂ４’ -R Ｂ４１’ or two R on the same atom Ｂ４’ In total, =O, =C(-L Ｂ４’ -R Ｂ４１’ ) ２ , =N-L Ｂ４’ -R Ｂ４１’ or optionally substituted =CH ２ or =NH, and each R Ｂ４１’ are independently -R', and W Ｘ４’ is O, S or Se, X ５’ is -C(R Ｂ５’ ) ２ -, -N(R Ｂ５’ ) -, -C(R Ｂ５’ ) = , -C(W Ｘ５’ )-, -N= or optionally substituted -NH-, -CH ２ - or -CH=, and each R Ｂ５’ are independently halogen, -CN, -NO ２ Or -L Ｂ５’ -R Ｂ５１’ and R Ｂ５１’ is -R', -N(R') ２ , -OR' or -SR', and W Ｘ５’ is O, S or Se, X ６’ is -C(R Ｂ６’ ) =, -C(OR Ｂ６’ ) = , -C(R Ｂ６’ ) ２ -, -C(W Ｘ６’ )-,-C(-N(R Ｂ６’ ) ２ )=, -N= or optionally substituted -NH-, -CH ２ - or -CH=, and each R Ｂ６’ are independently halogen, -CN, -NO ２ Or -L Ｂ６’ -R Ｂ６１’ or two R on the same atom Ｂ６’ In total, =O, =C(-L Ｂ６’ -R Ｂ６１’ ) ２ , =N-L Ｂ６’ -R Ｂ６１’ or optionally substituted =CH ２ or =NH, and each R Ｂ６１’ is independently R′, and W Ｘ６’ is O, S or Se, X ７’ is -C(R Ｂ７’ ) =, -C(OR Ｂ７’ ) = , -C(R Ｂ７’ ) ２ -, -C(W Ｘ７’ )-,-C(-N(R Ｂ７’ ) ２ ) = , -N(R Ｂ７’ )-, -N= or optionally substituted -NH-, -CH ２ - or -CH=, and each R Ｂ７’ are independently halogen, -CN, -NO ２ Or -L Ｂ７’ -R Ｂ７１’ or two R on the same atom Ｂ７’ In total, =O, =C(-L Ｂ７’ -R Ｂ７１’ ) ２ , =N-L Ｂ７’ -R Ｂ７１’ or optionally substituted =CH ２ or =NH, and each R Ｂ７１’ is independently R′; W Ｘ７’ is O, S or Se, X ８’ and X ９’ each is independently C or N; L Ｂ２’ , L Ｂ３’ , L Ｂ４’ , L Ｂ５’ , L Ｂ６’ and L Ｂ７’ Each of the groups independently represents L Ｂ and Each L Ｂ are independently a covalent bond or an optionally substituted divalent C １～１０ is a saturated or partially unsaturated chain, wherein one or more of the methylene units are optionally and independently -Cy-, -O-, -S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ is replaced by -N(R')-, -C(O)S- or -C(O)O-; each -Cy- is independently an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, -C(O)N(R), ２ Or -SO ２ R, and Each R is independently -H or C １～２０ Aliphatic, C with 1-10 heteroatoms １～２０ Heteroaliphatic, C ６～２０ Aryl, C ６～２０ Arylaliphatic, C with 1-10 heteroatoms ６～２０ an optionally substituted group selected from arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms, and 3-20 membered heterocyclyl having 1-10 heteroatoms; or two R groups optionally and independently combine to form a covalent bond, or two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said atom; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said intervening atoms; An oligonucleotide having the structure:

23. X １’ The oligonucleotide of claim 22, wherein is -N(-)-.

24. X ２’ The oligonucleotide of claim 23, wherein is -C(O)-.

25. X ３’ The oligonucleotide of claim 24, wherein is -NH-.

26. X １’ teeth, 【Chemistry 12】 23. The oligonucleotide of claim 22,

27. N ０ The oligonucleotide of claim 26, wherein the sugar is a 2'-OMe modified sugar.

28. N ０ The oligonucleotide of claim 26, wherein the sugar is a 2'-MOE modified sugar.

29. When the oligonucleotide is aligned with the target nucleic acid, N ０ is opposite the target adenosine.

30. N －１ is a nucleobase, 【Chemistry 13】 or BA comprises a ring BA or a tautomer thereof, wherein ring BA is of formula BA-III-e: 【Chemistry 14】 (In the formula, X １ is -N(-)- or -C(-)=, W Ｘ２ and W Ｘ６ each is independently O, S or Se; R Ｂ４ is halogen, -CN, -NO ２ Or -L Ｂ４ -R Ｂ４１ and R Ｂ４１ is R′, R Ｂ５ is halogen, -CN, -NO ２ Or -L Ｂ５ -R Ｂ５１ and R Ｂ５１ is -R', -N(R') ２ , -OR' or -SR', L Ｂ４ and L Ｂ５ Each of the groups independently represents L Ｂ and Each L Ｂ are independently a covalent bond or an optionally substituted divalent C １～１０ is a saturated or partially unsaturated chain, wherein one or more of the methylene units are optionally and independently -Cy-, -O-, -S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O) ２ -, -S(O) ２ is replaced by -N(R')-, -C(O)S- or -C(O)O-; each -Cy- is independently an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms; Each R' is independently -R, -C(O)R, -C(O)OR, -C(O)N(R), ２ Or -SO ２ R, and Each R is independently -H or C １～２０ Aliphatic, C with 1-10 heteroatoms １～２０ Heteroaliphatic, C ６～２０ Aryl, C ６～２０ Arylaliphatic, C with 1-10 heteroatoms ６～２０ an optionally substituted group selected from arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms, and 3-20 membered heterocyclyl having 1-10 heteroatoms; or two R groups optionally and independently combine to form a covalent bond, or two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said atom; or two or more R groups on two or more atoms optionally and independently combine with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to said intervening atoms; The oligonucleotide according to any one of claims 22 to 29, having the structure:

31. a first domain having a length of about 2 to 50 (e.g., about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50, etc.) nucleobases; 2. The oligonucleotide of claim 1, comprising a second domain having a length of from about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50 nucleobases, etc.

32. about 1 to 50 (e.g., about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50 or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or or about 5%-100% (e.g., about 10%-100%, 20-100%, 30%-100%, 40%-100%, 50%-80%, 50%-85%, 50%-90%, 50%-95%, 60%-65%, 70%-75%, 80%-85%, 85%-90%, 85%-95%, 90%-95%, 100%-10 ... % to 80%, 60% to 85%, 60% to 90%, 60% to 95%, 60% to 100%, 65% to 80%, 65% to 85%, 65% to 90%, 65% to 95%, 65% to 100%, 70% to 80%, 70% to 85%, 70% to 90%, 70% to 95%, 70% to 100%, 75% to 80%, 75% to 85%, 75% to 90%, 75% to 95%, 75% to 100%, 80% to 85 32. The oligonucleotide of any one of claims 1 to 31, wherein at least one of the oligonucleotides (e.g., 80%-90%, 80%-95%, 80%-100%, 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100%, 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%) comprises a 2'-F modification.

33. About 1 to 50 (e.g., about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50 or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40 or 50, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc., sugars in said oligonucleotide, or about 5%-100% (e.g., about 10%-100%, 20-100%, 30%-100%, 40%-100%, 50%-80%, 50%-85%, 50%-90%, 50%-90%, etc.) of the sugars in said oligonucleotide. 5%, 60% to 80%, 60% to 85%, 60% to 90%, 60% to 95%, 60% to 100%, 65% to 80%, 65% to 85%, 65% to 90%, 65% to 95%, 65% to 100%, 70% to 80%, 70% to 85%, 70% to 90%, 70% to 95%, 70% to 100%, 75% to 80%, 75% to 85%, 75% to 90%, 75% to 95%, 75% to 100%, 33. The oligonucleotide of claim 32, wherein 80%-85%, 80%-90%, 80%-95%, 80%-100%, 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100%, 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% (such as 2'-OMe modifications) comprise 2'-OMe modifications.

34. 34. The oligonucleotide of claim 33, comprising from about 1 to 50 (e.g., from about 5, 6, 7, 8, 9, or 10 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, or 50, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) sugars having 2'-MOE modifications.

35. About 5%-100% (e.g., about 10%-100%, 20-100%, 30%-100%, 40%-100%, 50%-80%, 50%-85%, 50%-90%, 50%-95%, 60%-80%, 60%-85%, 60%-90%, 60%-95%, 60%-100%, 65%-80%, 65%-85%, 65%-90%, 65%-95%, 65%-100%, 70%-80%, 70%-85%, 70%-90%, 70%-95%, 70% 35. The oligonucleotide of claim 34, wherein: up to 100%, 75% to 80%, 75% to 85%, 75% to 90%, 75% to 95%, 75% to 100%, 80% to 85%, 80% to 90%, 80% to 95%, 80% to 100%, 85% to 90%, 85% to 95%, 85% to 100%, 90% to 95%, 90% to 100%, 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% comprises a 2'-MOE modification.

36. one or more (e.g., 1-20, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 2-20, 3-15, 4-15, 5-15, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) 2'-F blocks and one or more (e.g., 1-20, 1-15, 1-14, 1-13, 1-12, 1-11, 1- 34. The oligonucleotide of claim 33, wherein the oligonucleotide comprises separation blocks of 2'-F or more (e.g., 10, 2-20, 3-15, 4-15, 5-15, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.), each sugar in each 2'-F block is independently a 2'-F modified sugar, and each sugar in each separation block is independently a sugar other than a 2'-F modified sugar.

37. The oligonucleotide of claim 36, wherein there are two or more 2'-F blocks in the oligonucleotide.

38. 38. The oligonucleotide of claim 37, wherein there are two or more separation blocks in the oligonucleotide.

39. 39. The oligonucleotide of claim 38, wherein each separation block independently comprises a 2'-OR modified sugar, wherein R is not -H.

40. Each sugar in each separation block is independently a 2'-OR modified sugar or a bicyclic sugar, where R is an optionally substituted C １～６ 39. The oligonucleotide of claim 38, which is aliphatic.

41. 39. The oligonucleotide of claim 38, wherein each sugar in the separation block is independently a 2'-OMe or a 2'-MOE modified sugar.

42. 40. The oligonucleotide of claim 39, wherein there are about 1, 2, 3, 4, or 5 2'-F modified sugars in each 2'-F block.

43. N ０ and there are 5 or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more) nucleosides on the 5' side of N ０ The oligonucleotide of claim 39, wherein there are 5 or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more) nucleosides on the 3' side of the

44. 5'-N ２ N １ N ０ N －１ N －２ -3', N ２ , N １ , N ０ , N －１ and N －２ is independently a nucleoside, and when the oligonucleotide is aligned with a target nucleic acid, N ０ is opposite the target adenosine.

45. N ０ The sugars may be natural DNA sugars, 2'-F modified sugars, 2'-OR modified sugars (wherein R is an optionally substituted C １～６ 45. The oligonucleotide of claim 44, wherein the sugar is aliphatic) or a bicyclic sugar.

46. N １ The sugars may be natural DNA sugars, 2'-F modified sugars, 2'-OR modified sugars (wherein R is an optionally substituted C １～６ 46. ​​The oligonucleotide of claim 45, wherein the sugar is aliphatic) or a bicyclic sugar.

47. N －１ The sugars may be natural DNA sugars, 2'-F modified sugars, 2'-OR modified sugars (wherein R is an optionally substituted C １～６ 47. The oligonucleotide of claim 46, wherein the sugar is aliphatic) or a bicyclic sugar.

48. N －１ 48. The oligonucleotide of claim 47, wherein said nucleobase is G.

49. N －１ 48. The oligonucleotide of claim 47, wherein said nucleobase is hypoxanthine.

50. N ２ and N １ The oligonucleotide of claim 44, wherein the internucleotide linkage between is a natural phosphate linkage, a PS internucleotide linkage (e.g., a phosphorothioate internucleotide linkage) or a PN internucleotide linkage (e.g., a phosphorylguanidine internucleotide linkage such as n001).

51. N １ and N ０ The oligonucleotide of claim 44, wherein the internucleotide linkage between is a natural phosphate linkage, a PS internucleotide linkage (e.g., a phosphorothioate internucleotide linkage) or a PN internucleotide linkage (e.g., a phosphorylguanidine internucleotide linkage such as n001).

52. N ０ and N －１ The oligonucleotide of claim 44, wherein the internucleotide linkage between is a natural phosphate linkage, a PS internucleotide linkage (e.g., a phosphorothioate internucleotide linkage) or a PN internucleotide linkage (e.g., a phosphorylguanidine internucleotide linkage such as n001).

53. N －１ and N －２ The oligonucleotide of claim 44, wherein the internucleotide linkage between is a natural phosphate linkage, a PS internucleotide linkage (e.g., a phosphorothioate internucleotide linkage) or a PN internucleotide linkage (e.g., a phosphorylguanidine internucleotide linkage such as n001).

54. 5'-N ２ N １ N ０ N －１ N －２ N －３ -3', N －３ is independently a nucleoside, and N －２ and N －３ The oligonucleotide of claim 39, wherein the internucleotide linkage between is a natural phosphate linkage, a PS internucleotide linkage (e.g., a phosphorothioate internucleotide linkage) or a PN internucleotide linkage (e.g., a phosphorylguanidine internucleotide linkage such as n001).

55. N －２ and N －３ 55. The oligonucleotide of claim 54, wherein the internucleotide linkage between is a natural phosphate linkage or a PS internucleotide linkage (e.g., a phosphorothioate internucleotide linkage).

56. 56. The oligonucleotide of any one of claims 1 to 55, wherein each internucleotide bond is independently selected from a PO bond, a PN bond and a PS bond.

57. 57. The oligonucleotide of any one of claims 1 to 56, comprising one or more PN bonds.

58. 58. The oligonucleotide of claim 57, wherein each PN internucleotide linkage is independently n001.

59. An oligonucleotide comprising at the position of the modified internucleotide linkage -O ５ -P Ｌ (R ＣＡ ) -O ３ - (In the formula, P Ｌ is P or P(=W), W is O, S or W Ｎ and R ＣＡ is or comprises an optionally substituted or capped chiral auxiliary moiety; O ５ is the oxygen attached to the 5'-carbon of the sugar, and O ３ is the oxygen attached to the 3'-carbon of the sugar.

59. An oligonucleotide which is otherwise identical to the oligonucleotide according to any one of claims 1 to 58, except that the linkage has the structure:

60. 60. The oligonucleotide of any one of claims 1 to 59, wherein each chiral internucleotide linkage is independently chiral controlled.

61. 61. A phosphoramidite, wherein the nucleobase of the phosphoramidite is a nucleobase or a tautomer thereof according to any one of claims 1 to 60, said nucleobase or tautomer thereof being optionally substituted or protected.

62. 13. A phosphoramidite, wherein the nucleobase of the phosphoramidite is or comprises a ring BA, wherein ring BA has the structure BA-I, BA-I-a, BA-I-b, BA-I-c, BA-I-d, BA-II, BA-II-a, BA-II-b, BA-II-c, BA-II-d, BA-III, BA-III-a, BA-III-b, BA-III-c, BA-III-d, BA-III-e, BA-IV, BA-IV-a, BA-IV-b, BA-V, BA-V-a, BA-V-b or BA-VI, or a tautomer of ring BA, and wherein the nucleobase is optionally substituted or protected.

63. 63. The phosphoramidite of claim 61 or 62, wherein the sugar of the phosphoramidite is a sugar according to any one of claims 1 to 60, said sugar being optionally protected.

64. R ＮＳ -P(OR)N(R) ２ R ＮＳ is an optionally protected nucleoside moiety, and each R is as described herein.

65. R ＮＳ -P(OCH ２ CH ２ CN)N(i-Pr) ２ 63. The phosphoramidite of claim 61 or 62 having the structure:

66. 65. A phosphoramidite according to any one of claims 61 to 64, comprising a chiral auxiliary moiety, wherein phosphorus is bonded to an oxygen and a nitrogen atom of the chiral auxiliary moiety.

67. 【Catalog 15】 The phosphoramidite according to any one of claims 61 to 64, having the structure:

68. 【Catalog 16】 A phosphoramidite having the structure:

69. A method for preparing an oligonucleotide or composition, comprising coupling an -OH group of an oligonucleotide or nucleoside with a phosphoramidite or compound according to any one of claims 61 to 68.

70. A pharmaceutical composition comprising or delivering an effective amount of the oligonucleotide of any one of claims 1 to 60, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

71. 1. An oligonucleotide composition comprising a plurality of oligonucleotides, the plurality of oligonucleotides comprising: 1) A common base sequence; 2) independently, the stereochemistry of the same linked phosphorus at one or more (e.g., about 1-50, 1-40, 1-30, 1-25, 1-20, 1-15, 1-10, 5-50, 5-40, 5-30, 5-25, 5-20, 5-15, 5-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 or more) chiral internucleotide linkages ("chirally controlled internucleotide linkages"); and each oligonucleotide of the plurality is independently an oligonucleotide of any one of claims 1 to 60, or an acid, base or salt form thereof.

72. 72. The oligonucleotide of claim 71, wherein each oligonucleotide of the plurality is independently in a pharma- ceutically acceptable salt form.

73. 73. The oligonucleotide of claim 71 or 72, wherein the multiple oligonucleotides are identical.

74. Of the oligonucleotides in the composition that share a common structure of the plurality, a percentage of the plurality is about or at least about (DS) ｎｃ 74. The oligonucleotide of claim 71, wherein DS is about 85% to 100% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% or more), and n is the number of chiral binding phosphorus.

75. The oligonucleotide of any one of claims 71 to 74, which is a pharmaceutical composition and comprises a pharma- ceutically acceptable carrier.

76. evaluating an agent or composition thereof in a cell, tissue or animal, the cell, tissue or animal being or comprising a cell, tissue or organ associated with a pathology, disorder or disease and / or comprising a nucleotide sequence associated with a pathology, disorder or disease; administering to a subject susceptible to or suffering from a condition, disorder, or disease an effective amount of an agent or composition for preventing or treating said condition, disorder, or disease; The method includes:

77. A method for characterizing an oligonucleotide or composition, comprising administering the oligonucleotide or composition to a cell or population thereof that contains or expresses an ADAR1 polypeptide or a characteristic portion thereof, or a polynucleotide encoding an ADAR1 polypeptide or a characteristic portion thereof.

78. A method of modifying a target adenosine in a target nucleic acid, comprising contacting said target nucleic acid with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75; or A method for deaminating a target adenosine in a target nucleic acid, comprising contacting said target nucleic acid with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75; or A method of producing or restoring or increasing the level of a product of a specific nucleic acid, comprising contacting a target nucleic acid with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein the target nucleic acid comprises a target adenosine and the specific nucleic acid differs from the target nucleic acid in that the specific nucleic acid has an I or a G in place of the target adenosine; or A method for reducing the level of a product of a target nucleic acid, comprising contacting the target nucleic acid with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein the target nucleic acid comprises a target adenosine; or A method for modulating a protein-protein interaction in a system in which a protein is translated from its coding RNA, comprising contacting said coding RNA with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein an adenosine in said coding RNA is edited and a protein is translated from said edited mRNA (an "edited protein"), said edited protein differing from the unedited protein at amino acid residues involved in said protein-protein interaction, or A method for modulating a protein interaction with a drug in a system in which a protein is translated from its coding RNA, comprising contacting said coding RNA with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein an adenosine in said coding RNA is edited and a protein is translated from said edited mRNA (an "edited protein"), said edited protein differing from the unedited protein at an amino acid residue involved in said protein-drug interaction, or A method for modulating a protein interaction with a drug in a system in which a protein is translated from its coding RNA, comprising administering to said system an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein an adenosine in said coding RNA is edited and a protein is translated from said edited mRNA (an "edited protein"), said edited protein differing from the unedited protein at an amino acid residue involved in said protein-drug interaction, or A method of modulating an interaction between a protein and its partner protein in a system, comprising administering to said system an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein said oligonucleotide or composition is capable of editing an adenosine in a nucleic acid encoding said protein or its partner protein, and wherein the edited nucleic acid encodes a protein which differs from a protein encoded by an unedited nucleic acid in at least one amino acid residue involved in said interaction between said protein and its partner protein; or A method for modulating the level, structure and / or activity of a nucleic acid and / or its encoded product in a system, comprising contacting said nucleic acid with an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein an adenosine in said nucleic acid is edited; or A method for modulating the level, structure and / or activity of a nucleic acid and / or the product encoded thereby in a system, comprising administering to said system an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75, wherein an adenosine in said nucleic acid is edited; or A method for editing a transcript in an immune cell, comprising administering to the immune cell an effective amount of an oligonucleotide or composition according to any one of claims 1 to 60 or 70 to 75; or A method of delivering an oligonucleotide to a system, comprising administering to said system a conjugate of said oligonucleotide with an additional chemical moiety or a salt thereof; A method for improving the editing level of an oligonucleotide, comprising incorporating a structural element according to any one of claims 1 to 60 or 70 to 75 or the present disclosure; or A compound, oligonucleotide, composition, nucleobase, sugar, nucleoside, internucleotide linkage or method described in the present disclosure.

79. A method of preventing or treating a condition, disorder or disease comprising administering or delivering to a subject susceptible to or suffering from the same an effective amount of an oligonucleotide or composition according to any one of claims 1-60, 70-75 or 78.

80. 80. The method of claim 79, wherein the condition, disorder or disease is associated with a G to A mutation.

81. 82. The method of claim 81, wherein the pathology, disorder or disease is a liver pathology, disorder or disease.

82. Use of an oligonucleotide or composition according to any one of claims 1 to 60, 70 to 75 or 78 for altering mRNA splicing, wherein the target adenosine of the mRNA is edited, used or Use of an oligonucleotide or composition according to any one of claims 1 to 60, 70 to 75 or 78 for silencing protein expression, wherein a target adenosine of an mRNA encoding the protein is edited, or Use of an oligonucleotide or composition according to any one of claims 1 to 60, 70 to 75 or 78 for repairing a nonsense mutation, wherein the target adenosine of an RNA is edited such that the nonsense mutation is repaired. Use of an oligonucleotide or composition according to any one of claims 1 to 60, 70 to 75 or 78 for repairing a missense mutation, wherein the target adenosine of the RNA is edited such that the missense mutation is repaired; or Use of an oligonucleotide or composition according to any one of claims 1 to 60, 70 to 75 or 78 for editing a target adenosine in a codon; or 80. Use of an oligonucleotide or composition according to any one of claims 1 to 60, 70 to 75 or 78 for editing a target adenosine in an upstream ORF.

83. An oligonucleotide, composition, phosphoramidite, compound, agent, method or use according to any one of the present specification or exemplary embodiments 1-2597.

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