Two series of conformationally constrained analogues from Gly(3) -MC62 were designed by scanning the residues Lys(1) , Thr(2) , Met(4) , Lys(5) , Met(7,) and Ala(8) with an i-(i + 2) lactam bridge consisting of a Glutamic acid-xaa-lysine (Glu-Xaa-Lys) scaffold and a diproline fragment. They were synthesized and evaluated for their antihyperglycemic effects. Through screening in normal and mice with diabetes mellitus, peptides II-5, III-3, III-4, and III-5 showed significant improvement in antihyperglycemic and antioxidative activities compared with Gly(3) -MC62, especially the compound III-4. The primary mechanism of the compounds (II-5, III-3, III-4, and III-5) underlying this effect is the islet β-cells against oxidative damage induced by STZ, and III-4-treated mice showed considerable improvement in the preservation of beta cells in the pancreatic islets of DM mice. These data suggested that III-4 could be candidate for the future treatment of diabetes mellitus.
Keywords: antihyperglycemic; antioxidative; lactam bridge; peptide Gly3-MC62.
© 2015 John Wiley & Sons A/S.