Design, Synthesis, and Biological Evaluation of Novel Peptide Gly3‐MC62 Analogues as Potential Antidiabetic Agents. (25th April 2015)

• Record Type: Journal Article
• Authors: Yang, Baowei; Zhang, Chenyu; Li, Xue; Yan, Sijia; Wei, Wei; Wang, Xuekun; Deng, Xin; Huang, Wenlong; Qian, Hai
• Is Part Of: Chemical biology & drug design. Volume 86:Number 5(2015:Nov.)
• Page Start: 979
• Page End: 989
• Publication Date: 2015-04-25
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12564
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12564-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Two series of conformationally constrained analogues from <bold>Gly</bold><sup><bold>3</bold></sup><bold>‐</bold><bold>MC</bold><bold>62</bold> were designed by scanning the residues Lys<sup>1</sup>, Thr<sup>2</sup>, Met<sup>4</sup>, Lys<sup>5</sup>, Met<sup>7, </sup> and Ala<sup>8</sup> 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 <bold>II</bold><bold>‐5</bold>, <bold>III</bold><bold>‐3</bold>, <bold>III</bold><bold>‐4</bold>, and <bold>III</bold><bold>‐5</bold> showed significant improvement in antihyperglycemic and antioxidative activities compared with <bold>Gly</bold><sup><bold>3</bold></sup><bold>‐</bold><bold>MC</bold><bold>62</bold>, especially the compound <bold>III</bold><bold>‐4</bold>. The primary mechanism of the compounds (<bold>II</bold><bold>‐5</bold>, <bold>III</bold><bold>‐3</bold>, <bold>III</bold><bold>‐4</bold>, and <bold>III</bold><bold>‐5</bold>) underlying this effect is the islet <italic>β</italic>‐cells against oxidative damage induced by STZ, and <bold>III</bold><bold>‐4</bold>‐treated mice showed considerable improvement in the preservation of beta cells in the pancreatic islets of DM mice. These data suggested that <bold>III</bold><bold>‐4</bold> could be candidate for the future treatment of diabetes mellitus.</p> </abstract>