Peptide analogs of alpha-melanocyte stimulating hormone

1. 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 a substantially pure compound that selectively binds melanocortin 1 receptor (MC1R), said compound comprising a polypeptide (SEQ ID NO:9) having the sequence:

Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Xaa 12 Xaa 13 ,

wherein Xaa 1 is D-Val, D-Ala or D-Lys;

Xaa 2 is D-Pro, D-Ala or D-Lys;

Xaa 3 is D-Lys, D-Orn, D-Nle, D-Ala or D-Lys;

Xaa 4 is Gly, or D-Ala;

Xaa 5 is D-Trp, Trp, D-3-benzothienyl-Ala, D-5-hydroxy-Trp, D-5-methoxy-Trp, D-Phe,-or-D-Ala;

Xaa 6 is D-Arg, D-His, or D-Ala;

Xaa 7 is D-Cha, D-Phe, Phe, D-4-fluoro-Phg, D-3-pyridyl-Ala, D-Thi, D-Trp, D-4-nitro-Phe, or D-Ala;

Xaa 8 is D-His, His, D-Arg, Phe, or D-Ala;

Xaa 9 is D-Glu, D-Asp, D-citrulline, D-Ser, or D-Ala;

Xaa 10 is D-Met, D-buthionine, D-Ile, or D-Ala;

Xaa 11 is D-Ser, D-Ile or D-Ala;

Xaa 12 is D-Tyr, D-Ser, or D-Ala; and

Xaa 13 is D-Ser or D-Ala;

wherein no more than one Xaa 1-13 is D-Ala except when Xaa 1-3 are all D-Ala, and no more than one Xaa 1-13 is an L-amino acid;

or a pharmaceutically acceptable salt thereof,

wherein said autoimmune disease or condition is selected from the group consisting of multiple sclerosis, diabetes type I, aplastic anemia, Grave's disease, celiac disese, Crohn's disease, lupus, arthritis, osteoarthritis, autoimmune uveitis and myasthenia gravis.

2. The method of claim 1 , said compound comprising a polypeptide (SEQ ID NO:11) having the sequence:

Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Xaa 12 Xaa 13 ,

wherein Xaa 1 is D-Val;

Xaa 2 is D-Pro;

Xaa 3 is D-Lys, D-Orn or D-Nle;

Xaa 4 is Gly;

Xaa 5 is D-Trp, Trp, D-3-benzothienyl-Ala, D-5-hydroxy-Trp, D-5-methoxy-Trp, or D-Phe;

Xaa 6 is D-Arg or D-His;

Xaa 7 is D-Cha, D-Phe, Phe, D-4-fluoro-Phg, D-3-pyridyl-Ala, D-Thi, D-Trp, or D-4-nitro-Phe;

Xaa 8 is D-His, His, D-Arg, Phe, or D-Ala;

Xaa 9 is D-Glu, D-Asp, D-citrulline or D-Ser;

Xaa 10 is D-Met, D-buthionine or D-Ile;

Xaa 11 is D-Ser or D-Ile;

Xaa 12 is D-Tyr or D-Ser; and

Xaa 13 is D-Ser;

wherein no more than one Xaa 1-13 is an L-amino acid;

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , said compound comprising a polypeptide (SEQ ID NO:12) having the sequence:

Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Xaa 12 Xaa 13 ,

wherein Xaa 1 is D-Val;

Xaa 2 is D-Pro;

Xaa 3 is D-Lys, D-Orn or D-Nle;

Xaa 4 is Gly;

Xaa 5 is D-Trp;

Xaa 6 is D-Arg;

Xaa 7 is D-Cha, D-Phe, or D-Thi;

Xaa 8 is D-His;

Xaa 9 is D-Glu or D-Ser;

Xaa 10 is D-Met, D-buthionine or D-Ile;

Xaa 11 is D-Ser or D-Ile;

Xaa 12 is D-Tyr or D-Ser; and

Xaa 13 is D-Ser;

wherein no more than one Xaa 1-13 is an L-amino acid;

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , said compound comprising a core tetrapeptide having the sequence:

D-Trp D-Arg Xaa D-His (SEQ ID NO:2),

wherein Xaa is D-Cha, D-Phe or Phe;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , said compound comprising a C-terminal polypeptide having the sequence: D-Ser D-Ile D-Ile D-Ser D-Ser (SEQ ID NO:3).

6. The method of claim 1 , said compound comprising a polypeptide having the sequence:

(SEQ ID NO: 5)

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Cha D-His

D-Ser D-Ile D-Ile D-Ser D-Ser;

or

(SEQ ID NO: 7)

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His

D-Glu D-Met D-Ser D-Tyr D-Ser;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein said polypeptide is PEGylated.

8. The method 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.

9. The method of claim 1 , wherein said compound is conjugated to a biologically active functional group.

10. The method of claim 1 , wherein the compound selectively binds melanocortin 1 receptor (MC1R) but not MC3R, MC4R, or MC5R.

11. The method of claim 10 , wherein said compound comprises a polypeptide (SEQ ID NO:11) having the sequence:

Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa 10 Xaa 11 Xaa 12 Xaa 13 ,

wherein Xaa 1 is D-Val;

Xaa 2 is D-Pro;

Xaa 3 is D-Lys, D-Orn or D-Nle;

Xaa 4 is Gly;

Xaa 5 is D-Trp, D-3-benzothienyl-Ala, D-5-hydroxy-Trp, D-5-methoxy-Trp, or D-Phe;

Xaa 6 is D-Arg or D-His;

Xaa 7 is D-Cha, D-Phe, D-4-fluoro-Phg, D-3-pyridyl-Ala, D-Thi, D-Trp, or D-4-nitro-Phe;

Xaa 8 is D-His, D-Arg, or D-Ala;

Xaa 9 is D-Glu, D-Asp, D-citrulline or D-Ser;

Xaa 10 is D-Met, D-buthionine or D-Ile;

Xaa 11 is D-Ser or D-Ile;

Xaa 12 is D-Tyr or D-Ser; and

Xaa 13 is D-Ser;

wherein no more than one Xaa 1-13 is an L-amino acid;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 10 , wherein said compound comprises a polypeptide (SEQ ID NO:12) having the sequence:

Xaa 1 Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaa io Xaa ii Xaa 12 Xaa 13 ,

wherein Xaa 1 is D-Val;

Xaa 2 is D-Pro;

Xaa 3 is D-Lys, D-Orn or D-Nle;

Xaa 4 is Gly;

Xaa 5 is D-Trp;

Xaa 6 is D-Arg;

Xaa 7 is D-Cha, D-Phe, or D-Thi;

Xaa 8 is D-His;

Xaa 9 is D-Glu or D-Ser;

Xaa 10 is D-Met, D-buthionine or D-Ile;

Xaa 11 is D-Ser or D-Ile;

Xaa 12 is D-Tyr or D-Ser; and

Xaa 13 is D-Ser;

wherein no more than one Xaa 1-13 is an L-amino acid;

or a pharmaceutically acceptable salt thereof.

13. The method of claim 10 , wherein said compound comprises a core tetrapeptide having the sequence:

D-Trp D-Arg Xaa D-His (SEQ ID NO:2),

wherein Xaa is D-Cha, D-Phe or Phe;

or a pharmaceutically acceptable salt thereof.

14. The method of claim 10 , wherein said compound comprises a C-terminal polypeptide having the sequence: D-Ser D-Ile D-Ile D-Ser D-Ser (SEQ ID NO:3).

15. The method of claim 10 , wherein said compound comprises a polypeptide having the sequence:

(SEQ ID NO: 5)

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Cha D-His

D-Ser D-Ile D-Ile D-Ser D-Ser; or

(SEQ ID NO: 7)

D-Val D-Pro D-Lys Gly D-Trp D-Arg D-Phe D-His

D-Glu D-Met D-Ser D-Tyr D-Ser;

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein said compound has an immunosuppressive activity in said subject.

17. The method of claim 1 , wherein said compound increases the cAMP level in a cell of said subject.

18. The method of claim 1 , wherein said compound suppresses production of a pro-inflammatory cytokine in said subject.

19. The method of claim 18 , wherein said pro-inflammatory cytokine is selected from the group consisting of TNF-α, IL-10, IFNγ, IL-6, IL-12, and monocyte chemotactic protein (MCP)-1.