Design, Synthesis, and Biological Evaluation of Novel Peptide Gly3‐MC62 Analogues as Potential Antidiabetic Agents
Design, Synthesis, and Biological Evaluation of Novel Peptide Gly3‐MC62 Analogues as Potential Antidiabetic Agents
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DOI：
10.1111/cbdd.12564
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发表时间：
2015-11
影响因子：
3
通讯作者：
Baowei Yang;Chenyu Zhang;Xue Li;Sijia Yan;Wei Wei-Wei;Xuekun Wang;Xin Deng;Wen-long Huang;Hai Qian
中科院分区：
文献类型：
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作者：
Baowei Yang;Chenyu Zhang;Xue Li;Sijia Yan;Wei Wei-Wei;Xuekun Wang;Xin Deng;Wen-long Huang;Hai Qian
通过用i-（i + 2）内酰胺桥（由谷氨酸-xaa-赖氨酸（Glu-Xaa-Lys）支架和二脯氨酸片段组成）扫描残基Lys 1、Thr 2、Met 4、Lys 5、Met 7和Ala 8，设计了来自Gly 3-MC 62的两个系列构象受限的类似物。合成并评价了它们的降血糖作用。通过在正常小鼠和糖尿病小鼠中筛选，与Gly 3-MC 62相比，肽II-5、III-3、III-4和III-5显示出显著改善的抗高血糖和抗氧化活性，尤其是化合物III-4。化合物（II-5、III-3、III-4和III-5）的主要作用机制是胰岛β细胞对抗STZ诱导的氧化损伤，III-4处理的小鼠在DM小鼠胰岛β细胞的保存方面表现出相当大的改善。这些数据表明，III-4可能是未来治疗糖尿病的候选药物。
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.