Peptide analogs of alpha-melanocyte stimulating hormone

Abstract

Provided herein are stable peptide analogs of the native alpha-melanocyte stimulating hormone (α-MSH) having selectivity for the melanocortin 1 receptor (MC1R). Also provided herein are pharmaceutical preparations of the α-MSH peptide analogs, as well as methods of using these analogs in the treatment of medical and veterinary conditions involving MC1R.

The invention claimed is: 
     
       1. A compound that selectively binds melanocortin 1 receptor (MC1R), said compound comprising a core tetrapeptide having the sequence:
 His Xaa Arg Trp (SEQ ID NO: 1), 
 wherein Xaa is D-Cha or Cha; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. The compound of  claim 1 , said compound comprising a polypeptide having the sequence: Ser Tyr Ser Met Glu His Cha Arg Trp Gly Lys Pro Val (SEQ ID NO: 6). 
     
     
       3. A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
       4. The compound of  claim 1 , wherein said compound is conjugated to a biologically active moiety. 
     
     
       5. The compound of  claim 1 , wherein said compound is PEGylated. 
     
     
       6. The compound of  claim 1 , wherein said compound exhibits at least one of the following properties:
 ability to selectively activate MC1R; 
 stability in plasma in vitro; or 
 resistance to protease degradation. 
 
     
     
       7. The compound of  claim 2 , wherein said compound is PEGylated. 
     
     
       8. The compound of  claim 2 , wherein said compound exhibits at least one of the following properties:
 ability to selectively activate MC1R; 
 stability in plasma in vitro; or 
 resistance to protease degradation. 
 
     
     
       9. A method of treating an autoimmune disease or condition in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 1 , wherein said autoimmune disease or condition is selected from the group consisting of multiple sclerosis, diabetes type I, aplastic anemia, Grave's disease, coeliac disease, Crohn's disease, lupus, arthritis, osteoarthritis, autoimmune uveitis and myasthenia gravis. 
     
     
       10. A method of treating inflammation in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 1 . 
     
     
       11. The method of  claim 10 , wherein said inflammation is associated with a disease selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, allergy, atherosclerosis, psoriasis, gastritis and ischemic heart disease. 
     
     
       12. A method for reducing or inhibiting transplant rejection in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 1 . 
     
     
       13. A method of treating melanoma in a subject in need thereof comprising administering to said subject a pharmaceutical comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 1 . 
     
     
       14. The method of  claim 13 , wherein the compound is conjugated to an anti-tumor payload. 
     
     
       15. A method of treating an autoimmune disease or condition in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 2 , wherein said autoimmune disease or condition is selected from the group consisting of multiple sclerosis, diabetes type I, aplastic anemia, Grave's disease, coeliac disease, Crohn's disease, lupus, arthritis, osteoarthritis, autoimmune uveitis and myasthenia gravis. 
     
     
       16. A method of treating inflammation in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 2 . 
     
     
       17. The method of  claim 16 , wherein said inflammation is associated with a disease selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, allergy, atherosclerosis, psoriasis, gastritis and ischemic heart disease. 
     
     
       18. A method for reducing or inhibiting transplant rejection in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 2 . 
     
     
       19. A method of treating melanoma in a subject in need thereof comprising administering to said subject a pharmaceutical comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of  claim 2 . 
     
     
       20. The method of  claim 19 , wherein the compound is conjugated to an anti-tumor payload.