Conotoxin peptide analogs and uses for the treatment of pain and inflammatory conditions
Provided herein are alpha-conotoxin peptide analogs, including alpha-conotoxin peptide analogs that are covalently attached to polyethylene glycol (PEG), and pharmaceutical compositions of such alpha-conotoxin peptide analogs. Also provided herein are methods of treating or preventing a condition conducive to treatment or prevention by inhibition of an α9-containing nicotinic acetylcholine receptor (nAChR) (e.g., the α9α10 subtype of the nAChR) in a subject.
1. A PEGylated conotoxin peptide analog or pharmaceutically acceptable salt thereof, wherein the conotoxin peptide analog is of Formula (Ia) (SEQ ID NO:94)
wherein R 1 is OH,
wherein the conotoxin peptide analog is covalently attached directly or via a linking group to one polyethylene glycol (PEG) polymer;
wherein the PEG polymer is covalently attached to the N-terminus of the conotoxin peptide analog; and
wherein the PEG polymer has a molecular weight in the range of 10 kDa to 40 kDa.
2. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 , wherein the PEG polymer is covalently attached to the conotoxin peptide analog via a linking group.
3. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 2 , wherein the linking group is a valerate linker having a formula of
4. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 , wherein the PEG polymer is a linear PEG polymer.
5. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 , wherein the PEG polymer has a molecular weight of 30 kDa.
6. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 5 , wherein the PEG polymer is a linear PEG polymer.
7. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 , wherein the PEGylated conotoxin peptide analog is of Formula (IIa) (SEQ ID NO:83):
8. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 7 , and a pharmaceutically acceptable carrier.
9. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 7 .
10. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 , and a pharmaceutically acceptable carrier.
11. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 .
12. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 2 , and a pharmaceutically acceptable carrier.
13. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 2 .
14. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 3 , and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 4 , and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 5 , and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 6 , and a pharmaceutically acceptable carrier.
18. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 3 .
19. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 4 .
20. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 5 .
21. A method of treating pain in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 6 .
22. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 1 .
23. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 7 .
24. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 2 .
25. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 3 .
26. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 4 .
27. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 5 .
28. A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 6 .