Nucleic acid conjugates and uses thereof
Provided herein are conjugates comprising targeting moieties such as sugars, folates and cell-penetrating peptides, which can be used for the improved delivery of agents (e.g., nucleic acids, such as oligonucleotides or mRNAs, or other agents) to cells. The invention provides conjugates and compounds comprising targeting moieties, methods for preparing the same, and intermediates useful in their preparation. In another aspect, the present invention provides formulations (e.g., pharmaceutical compositions) comprising the targeting moiety-containing conjugates and compounds. The present invention also provides methods for delivering agents (e.g., nucleic acids such as oligonucleotides or mRNAs) to a cell, methods for treating and/or preventing a disease or condition in a subject, and methods for modulating gene expression in a cell or a subject. Further, provided herein are kits comprising the conjugates, or formulations thereof; and kits for the preparation of conjugates described herein.
1. A conjugate of Formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
A is a group comprising a nucleic acid;
X is O or S;
each of L 1 , L 2 , and L 3 is independently, optionally substituted alkylene, or optionally substituted heteroalkylene;
n is an integer from 4 to 10, inclusive;
each instance of R N is independently hydrogen, optionally substituted alkyl; optionally substituted acyl; or a nitrogen protecting group; and
each instance of R O is independently hydrogen, optionally substituted alkyl; optionally substituted acyl; or an oxygen protecting group.
2. The conjugate of claim 1 , wherein
the conjugate is of Formula (V-a):
or a pharmaceutically acceptable salt thereof, wherein:
m is an integer from 0 to 10, inclusive; and
p is an integer from 0 to 10, inclusive.
3. The conjugate of claim 1 , wherein each instance of L 1 is independently optionally substituted heteroalkylene.
4. The conjugate of claim 1 , wherein L 2 is optionally substituted heteroalkylene.
5. The conjugate of claim 1 , wherein L 3 is optionally substituted alkylene.
6. The conjugate of claim 1 , wherein group A comprises:
(i) a cleavable linker covalently linked to the nucleic acid;
(ii) a single-stranded oligonucleotide;
(iii) a double-stranded oligonucleotide;
(iv) an antisense oligonucleotide;
(v) an mRNA; or
(vi) a lipid nanoparticle component selected from a cationic lipid, a non-cationic lipid and a conjugated lipid.
7. A pharmaceutical composition comprising a conjugate of claim 1 , and a pharmaceutically acceptable carrier or excipient.
8. A method of delivering a nucleic acid to a cell, the method comprising contacting the cell with a conjugate of claim 1 .
9. A method of delivering a nucleic acid to a subject, the method comprising administering to the subject a conjugate of claim 1 .
10. The conjugate of claim 1 , wherein the conjugate is of Formula (V-d):
or a pharmaceutically acceptable salt thereof.
11. The conjugate of claim 1 , wherein the conjugate is of Formula (V-e):
or a pharmaceutically acceptable salt thereof.
12. The conjugate of claim 1 , wherein the conjugate is of Formula (V-f):
or a pharmaceutically acceptable salt thereof.
13. The conjugate of claim 1 , wherein the conjugate is of Formula (V-g):
or a pharmaceutically acceptable salt thereof.
14. The conjugate of claim 1 , wherein the conjugate is of Formula (V-h):
or a pharmaceutically acceptable salt thereof.
15. The conjugate of claim 1 , wherein the conjugate is of Formula (V-i):
or a pharmaceutically acceptable salt thereof.
16. The conjugate of claim 1 , wherein the conjugate is of Formula (V-j):
or a pharmaceutically acceptable salt thereof.
17. The conjugate of claim 1 , wherein the conjugate is of Formula (V-k):
or a pharmaceutically acceptable salt thereof.
18. The conjugate of claim 15 , wherein, X is S and A is an oligonucleotide having the sequence of SEQ ID NO: 8.
19. The conjugate of claim 15 , wherein X is O and A is an oligonucleotide having the sequence of SEQ ID NO: 9.