Bcl-2促凋亡蛋白是线粒体凋亡通路的关键调控分子。该家族成员Bad被发现能够通过其BH3结构域核心肽段及其模拟肽激活葡萄糖激酶而恢复胰岛β细胞的数量和功能，促进胰岛素分泌；申请人前期研究亦发现该家族的另一成员Bim的BH3模拟肽能够同时抑制糖尿病靶点α-糖苷酶和PTP1B。本课题从“结构决定功能”的角度出发，提出结构上保守、相似的Bcl-2家族促凋亡蛋白BH3核心肽段及其类似物具有相似的葡糖糖激酶激活或α-糖苷酶/PTP1B抑制活性，具有潜在的抗糖尿病活性的假设。为验证该假设，拟将具有同源性和保守性的Bcl-2家族促凋亡蛋白BH3核心肽段进行模拟肽衍生合成、靶点确认和先导筛选研究，并进行先导二次优化衍生、生物活性筛选确定优选化合物，以期阐明Bcl-2促凋亡蛋白BH3模拟肽的新的作用靶点和体内抗糖尿病活性，为Bcl-2促凋亡蛋白生物学功能研究和降糖药物开发提供新思路。

The pro-apoptotic Bcl-2 proteins are key regulators of the mitochondrial apoptotic pathway. The BH3 domain core region and its peptidomimetics of Bad are found to show dual role in insulin secretion and β cell survival via activating glucokinase in diabetes. In our previous work, we have found that a BH3 peptididomimetics derived from another pro-apoptotic Bcl-2 protein Bim showed dual α-glucosidase/PTP1B inhibiton activity and in vivo anti-T2DM effect. From the view of "structure determines function", we proposed a hypothesis that the BH3 core region and its peptidomimetics of pro-apoptotic Bcl-2 proteins with consevered and similar sequences might show similar glucokinase activation and/or α-glucosidase/PTP1B inhibition activity. To validate this hypothesis, we proposed to design and synthesize BH3 peptidomimetics derived from all pro-apoptotic Bcl-2 proteins and map their possible targets in order to select the lead compound(s). Afterwards, the optimization of selected lead(s) and evaluation of their anti-T2DM effect will be conducted to obtain the candidate(s). These studies will contribute to the reveal of T2DM-related tas) of BH3 peptidomimetics and provide proof of the new functions of pro-apoptotic Bcl-2 proteins and novel discovery method of anti-T2DM drugs.