Targeting ligands for therapeutic compounds
Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds, that are useful in directing the compounds to the target in vivo. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to an expression-inhibiting oligomeric compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.
1. A targeting ligand comprising the structure of Formula B:
wherein n is an integer from 1 to 20; X is O, S, or NH; and Targeting Moiety is selected from the group consisting of: N-acetyl-galactosamine, galactose, galactosamine, N-formyl-galactosamine, N-propionyl-galactosamine, N-n-butanoylgalactosamine, and N-iso-butanoylgalactosamine.
2. The targeting ligand of claim 1 , comprising the following structure:
wherein n is an integer from 1 to 20 (Structure 1).
3. The targeting ligand of claim 1 , wherein the targeting ligand comprises the structure selected from:
4. The targeting ligand of claim 1 , wherein the Targeting Moiety is
5. The targeting ligand of claim 1 , wherein n is 6.
6. The targeting ligand of claim 1 , wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound.
7. The targeting ligand of claim 6 , wherein the expression-inhibiting oligomeric compound is an RNAi agent.
8. The targeting ligand of claim 7 , wherein the RNAi agent is double stranded.
9. The targeting ligand of claim 8 , wherein the RNAi agent comprises one or more modified nucleotides.
10. The targeting ligand claim 7 , wherein the targeting ligand is linked at the 3′ or 5′ terminal end of the RNAi agent.
11. The targeting ligand of claim 10 , wherein the RNAi agent is double stranded.
12. The targeting ligand of claim 11 , wherein the double-stranded RNAi agent is linked to the targeting ligand at the 5′ terminal end of the sense strand of the RNAi agent.
13. The targeting ligand of claim 7 , wherein the RNAi agent is linked to targeting ligand via a phosphate group, phosphorothioate group, or a phosphonate group.
14. A composition comprising the targeting ligand of claim 1 , wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound, wherein the structure of the targeting ligand and expression-inhibiting oligomeric compound is represented by the structure selected from the group consisting of:
wherein Z includes or consists of an expression-inhibiting oligomeric compound (Structure 101a);
wherein Z includes or consists of an expression-inhibiting oligomeric compound (Structure 102a); and
wherein Z includes or consists of an expression-inhibiting oligomeric compound (Structure 103a).
15. The composition of claim 14 , wherein the expression-inhibiting oligomeric compound is a double-stranded RNAi agent.
16. The composition of claim 15 , wherein the double-stranded RNAi agent is attached to the targeting ligand at the 5′ end of the sense strand of the RNAi agent.
17. A compound having the structure of:
wherein n is an integer from 1 to 20 (Structure 1d).
18. The compound of claim 17 , having the structure selected from the group consisting of:
19. The compound of claim 18 , wherein the compound is:
20. A method of inhibiting expression of a target nucleic acid in a subject, the method comprising administering a therapeutic amount of an expression-inhibiting oligomeric compound conjugated to the targeting ligand of claim 1 .
21. A method of introducing an expression-inhibiting oligomeric compound into a mammalian cell, the method comprising contacting a mammalian cell with the targeting ligand of claim 1 , linked to the expression-inhibiting oligomeric compound.
22. The method of claim 21 , wherein the cell is present in a subject.
23. The method of claim 22 , wherein the subject is a human.
24. The method of claim 21 , wherein the expression-inhibiting oligomeric compound is an RNAi agent.
25. A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the targeting ligand of claim 1 linked to an expression-inhibiting oligomeric compound to a subject in need of treatment thereof.
26. The method of claim 25 , wherein the expression-inhibiting oligomeric compound is an RNAi agent.
27. A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the composition of claim 14 to a subject in need of treatment thereof.