Design, Synthesis, and Biological Evaluation of Novel Peptide Gly3‐MC62 Analogues as Potential Antidiabetic Agents

Two series of conformationally constrained analogues from Gly3-MC62 were designed by scanning the residues Lys1, Thr2, Met4, Lys5, Met7, and Ala8 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 Gly3-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.