Discovery of Novel PTP1B Inhibitors Derived from the BH3 Domain of Proapoptotic Bcl-2 Proteins with Antidiabetic Potency
Discovery of Novel PTP1B Inhibitors Derived from the BH3 Domain of Proapoptotic Bcl-2 Proteins with Antidiabetic Potency
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发现源自促凋亡 Bcl-2 蛋白 BH3 结构域的新型 PTP1B 抑制剂，具有抗糖尿病功效
DOI：
10.1021/acsmedchemlett.1c00174
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Su Xianbin
中科院分区：
文献类型：
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作者：
Zhang Chuanliang;Wu Lijuan;Liu Xiaochun;Gao Jiangming;Liu Shan;Wu Juan;Huang Dingmin;Wang Zhenwei;Su Xianbin
BH3多肽类似物通过靶向抗细胞凋亡的Bcl-2蛋白而被普遍认为具有巨大的治疗癌症的潜力。在这里，我们描述了一类来源于促凋亡蛋白BH3结构域核心区域(h1-h4)的棕榈酰化多肽BH3类似物的合成和鉴定，并在体内外作为具有抗糖尿病活性的PTP1B抑制剂。PTP1B抑制剂在治疗2型糖尿病方面很有吸引力。我们使用简单的脂化方法设计了类似物，并在体内外发现了具有良好降糖活性的新的铅类似物。本文介绍的结果将BH3多肽类似物的替代靶点和功能从一个成员的BIM扩展到促凋亡的Bcl2蛋白的其他成员，并强调了它们在T2 DM中的治疗潜力。此外，我们的研究结果可能为Bcl2家族蛋白在线粒体营养和能量代谢中的调节功能提供新的证据。
BH3 peptide analogues are generally believed to exhibit great potency as cancer therapeutics via targeting antiapoptotic Bcl-2 proteins. Here, we describe the synthesis and identification of a new class of palmitoylated peptide BH3 analogues derived from the core region (h1–h4) of BH3 domains of proapoptotic Bcl-2 proteins and as alternative PTP1B inhibitors with antidiabetic potencyin vitroandin vivo. PTP1B inhibitors are attractive for treatment of type 2 diabetes. We design the analogues using a simple lipidation approach and discovered novel lead analogues with promising antidiabetic potencyin vitroandin vivo. The results presented here expanded the alternative target and function for the BH3 peptide analogues from one member Bim to other members of the proapoptotic Bcl-2 proteins and emphasize their therapeutic potential in T2DM. Furthermore, our findings may provide new proof of the regulatory function of Bcl-2 family proteins in mitochondrial nutrient and energy metabolism.