Fragment analogs as better mimics of obestatin

Obestatin is a twenty three amino acid peptide produced in the stomach by post translational modification of the preproghrelin gene. Since its discovery in 2005, many studies have shown that obestatin reduces feed intake and gain in body weight in rodents. Studies from our laboratory have shown the N-terminal thirteen residues mimic obestatin the best and residues 6-18 reduce epididymal fat significantly in adult male mice. In this study we have tried to increase the efficacy of these fragments. As an initial step, we have substituted G(8) with alpha-aminoisobutyricacid(Aib,U) and F(5) with cyclohexylalanine(Cha) in the N-terminal peptide to obtain two modified peptides and modified the middle fragment (residues 6-18) by substituting both the glycine residues at position 3 and 8 with alpha-aminoisobutyricacid(U). The rationale being, unusual amino acids could protect the peptides from immediate degradation and Aib would also induce secondary structure in these unstructured peptides. The N-terminal fragment with the G(8)U substitution fared the best. It reduced food intake, gain in body weight, levels of cholesterol and triglycerides in the blood, epididymal and perirenal fat in adult male mice similar to that of obestatin. The middle fragment with G(3,8)U double substitution was the second best.