Modified iRNA agents
View Patent ↗The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose. The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a carbohydrate; or a steroid, e.g., cholesterol, which is optionally substituted with at least one carbohydrate. is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.
1. An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (I) is incorporated into at least one of said strands:
wherein:
X is N(CO)R 7 , or NR 7 ;
Each of R 3 and R 9 is, independently, H, OR a , or OR b , provided that only one of R 3 or R 9 is OH, OR a , or OR b ;
R 5 is H, or C 1 -C 6 alkyl;
R 7 is C 1 -C 20 alkyl substituted with NR c R d or NHC(O)R d ;
R a is H or:
R b is H or:
Each of A and C is, independently, O or S;
B is OH, O − , or
R c is H or C 1 -C 6 alkyl; and
R d is a carbohydrate radical.
2. The compound of claim 1 , wherein R 3 is OR a .
3. The compound of claim 2 , wherein
and R 3 are trans.
4. The compound of claim 2 , wherein A is O.
5. The compound of claim 2 , wherein A is S.
6. The compound of claim 1 , wherein R 3 is OR b .
7. The compound of claim 2 , wherein R 7 is (CH 2 ) 5 NHR d or (CH 2 ) 5 NHC(O)R d .
8. The compound of claim 2 , wherein R d is chosen from the group of a galactose radical, an N-acetylgalactose radical, or a mannose radical.
9. The compound of claim 1 , wherein R 9 is OR a .
10. The iRNA agent of claim 9 , wherein
and R 9 are trans.
11. The iRNA agent of claim 1 , wherein R 9 is OR b .
12. An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (I′) is incorporated into at least one of said strands:
wherein:
X is N(CO)R 7 or NR 7 ;
R 9 is OR a , OR b or OH;
R 7 is R d ; or C 1 -C 20 alkyl substituted with NR c R d or NHC(O)R d ;
R a is H or
R b is H or
each of A and C is, independently, O or S; and
B is OH, O − , or
R c is H or C 1 -C 6 alkyl;
R d is a carbohydrate radical.
13. The iRNA agent of claim 12 , wherein R 9 is OR a .
14. The iRNA agent of claim 12 , wherein R 9 is OR b .
15. The iRNA agent of claim 12 , wherein
and R 9 are trans.
16. The iRNA agent of claim 1 , wherein X is N(CO)R 7 .
17. The iRNA agent of claim 16 , wherein R 7 is a C 3 -C 8 alkyl substituted with NHC(O)R d .
18. The iRNA agent of claim 17 , wherein R d is chosen from the group of a galactose radical, an N-acetylgalactose radical, or a mannose radical.
19. The iRNA agent of claim 1 , wherein A is O in each occurrence.
20. The iRNA agent of claim 1 , wherein A is S in at least one occurrence.