Methods for synthesis and uses of inhibitors of ghrelin O-acyltransferase as potential therapeutic agents for obesity and diabetes
The invention provides inhibitors of ghrelin O-acyltransferase, and methods of making and using them. In some embodiments, the invention provides bisubstrate analog inhibitors of ghrelin O-acyltransferase, which can be effective in treating, for example, obesity and diabetes mellitus.
1. A compound of the formula (I):
wherein R is absent, or is an organic moiety selected from the group consisting of a substituted or unsubstituted alkyl group, and a substituted or unsubstituted peptide chain and wherein TAT is the peptide shown in SEQ ID NO:3.
2. The compound of claim 1 , wherein R is a peptide of 12 amino acid residues so that the peptide GS to TAT is represented by SEQ ID NO:21.
3. The compound of claim 1 , wherein R is a peptide of 7 amino acid residues corresponding to ghrelin residues 4 through 10 so that the peptide GS to TAT is represented by SEQ ID NO:22.
4. The compound of claim 1 , wherein R is a peptide of 12 amino acid residues corresponding to ghrelin residues 4 through 15 so that the peptide GS to TAT is represented by SEQ ID NO:23.
5. A composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient or carrier.
6. A method for preparing the compound of one of claim 1 , comprising the steps of:
providing a ghrelin peptide sequence comprising from 3 to 15 N-terminal amino acid residues, wherein the serine residue at the 3 position is replaced with alloc-protected 1,2-diaminopropionic acid and wherein D4-Tat (“D4” disclosed as SEQ ID No:26) is bound to one end of the peptide sequence (SEQ ID NO: 26);
combining the ghrelin peptide sequence with Pd(PPh 3 ) 4 palladium reagent, n-bromo octanoic anhydride and Reagent K in one or more reaction vessels to obtain a bromo-octanoylated intermediate; and
combining the bromo-octanoylated intermediate with coenzyme A.
7. A method for treating obesity comprising administering to a subject a composition comprising a therapeutically effective amount of the composition of claim 3 , wherein Xaa at position 11 of SEQ ID NO:22 is Ahx.
8. The method of claim 7 , wherein administering the composition brings about a greater loss of fat mass than lean mass in the subject.
9. The method of claim 7 , wherein administering the composition brings about an increase in the ratio of ghrelin to acyl-ghrelin in the subject.
10. The method of claim 7 , wherein the therapeutically effective amount is at least about 5 mg/kg subject body weight.
11. The method of claim 7 , wherein the therapeutically effective amount is at least about 25 mg/kg subject body weight.
12. A method for treating Type II diabetes comprising administering to a subject a composition comprising a therapeutically effective amount of the composition of claim 3 , wherein Xaa at position 11 of SEQ ID NO:22 is Ahx.
13. The method of claim 12 , wherein administering the composition brings about an increased production of insulin in the subject.
14. The method of claim 12 , wherein administering the composition brings about a reduction in uncoupling-protein 2 (UCP-2) mRNA levels in the subject.
15. The method of claim 12 , wherein the therapeutically effective amount is at least about 5 mg/kg subject body weight.
16. The method of claim 12 , wherein the therapeutically effective amount is at least about 25 mg/kg subject body weight.
17. A kit comprising a composition comprising at least one dose of a therapeutically effective amount of the compound of claim 1 .