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View Patent ↗The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose.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 lipophilic moiety. e.g., cholesterol, 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, and at least one of said strands leads to the cleavage of a complementary target sequence via a RISC dependent mechanism:
wherein:
X is N(CO)R 7 , or NR 7 ;
R 3 and R 9 are each independently H, OH, 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
R b is
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; and
R d is a steroid radical, which is optionally tethered to at least one 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 a cholesterol radical.
9. The compound of claim 1 , wherein R 9 is OR a .
10. The compound of claim 9 , wherein
and R 9 are trans.
11. The compound of claim 1 , wherein R 9 is OR b .
12. The compound of claim 1 , wherein one of R 3 and R 9 is OR a .
13. The compound of claim 1 , wherein one of R 3 and R 9 is OR b .
14. A kit comprising an iRNA agent of claim 1 , a sterile container in which the iRNA agent is enclosed, and instructions for use.
15. The compound of claim 1 , wherein one of R 3 or R 9 is OH.
16. 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
R b is
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 steroid radical, which is optionally tethered to at least one carbohydrate radical; and
R d is a steroid radical, which is optionally tethered to at least one carbohydrate radical.
17. The compound of claim 16 , wherein R 9 is OH.
18. The compound of claim 16 , wherein R 9 is OR a .
19. The compound of claim 16 , wherein R 9 is OR b .
20. The compound of claim 16 , wherein
and R 9 are trans.
21. The compound of claim 1 , wherein R 3 is H, R 5 is H, and R 9 is OH.
22. The compound of claim 1 , wherein X is N(CO)R 7 .
23. The compound of claim 22 , wherein R 7 is a C 1 -C 20 alkyl substituted with NHC(O)R d .
24. The compound of claim 23 , wherein R 7 is a C 3 -C 8 alkyl substituted with NHC(O)R d .
25. The compound of claim 24 , wherein R 7 is a C 5 -C 7 alkyl substituted with NHC(O)R d .
26. The compound of claim 23 , wherein R 7 is a C 5 alkyl substituted with NHC(O)R d .
27. The compound of claim 26 , wherein R d is a cholesterol radical.
28. The compound of claim 27 , wherein R 9 is OH.
29. The compound of claim 1 , wherein R d is a cholesterol radical.
30. The agent of claim 1 , wherein R d is uvaol.
31. The agent of claim 1 , wherein R d is hecogenin.
32. The agent of claim 1 , wherein R d is diosgenin.
33. The agent of claim 1 , wherein R d is cholic acid.
34. The agent of claim 1 , wherein R d is dihydrotestosterone.
35. The agent of claim 1 , wherein R d is a cholesteryl residue.
36. The agent of claim 1 , wherein R d is an O3-(oleoyl)lithocholic acid residue.
37. The agent of claim 1 , wherein R d is an O3-(oleoyl) cholenic acid residue.
38. The agent of claim 1 , wherein A is O in each occurrence.
39. The agent of claim 1 , wherein A is S in at least one occurrence.
40. The agent of claim 1 , wherein formula (I) is incorporated into a sense strand.
41. The agent of claim 40 , wherein formula (I) is incorporated into the 3′ end of the sense strand.
42. The agent of claim 1 , wherein formula (I) is incorporated into an antisense strand.
43. The agent of claim 42 , wherein formula (I) is incorporated into the 3′ end of the antisense strand.