Design, synthesis and biological evaluation of novel peptide MC2 analogues from Momordica charantia as potential anti-diabetic agents

摘要

Three series of Momordica charantia (MC)2 analogues were designed, synthesized and evaluated for their anti-hyperglycaemic effects. Alanine scanning focusing on the peptide MC2 indicated the importance of the residues proline (Pro)~3, serine (Ser)~6, isoleucine (Ile)~7 and Ser~(10) for anti-hyperglycaemic effects. Among the first series of MC2 analogues, peptide Ⅰ-4 exhibited a better anti-hyperglycaemic effect and was chosen for further modification. A further two series of conformationally constrained analogues were designed by scanning the residues Pro~3, Ser~6, Ile~7, and Ser~(10) with an ⅰ - (ⅰ + 2) lactam bridge consisting of a glutamic acid-Xaa-lysine (Glu-Xaa-Lys) scaffold and a diproline fragment. By screening in normal mice and mice with diabetes mellitus, peptides Ⅱ-1, Ⅱ-2 and Ⅲ-3 showed a significant improvement in anti-hyperglycaemic and anti-oxidative activities compared with Ⅰ-4. These data suggest that Ⅱ-1, Ⅱ-2 and Ⅲ-3 could be candidates for future treatment of diabetes mellitus.