毛地黄鼠尾草中蛋白酪氨酸磷酸酶-1B抑制剂的发现及其作用机制的研究

近年的研究显示蛋白酪氨酸磷酸酶-1B(PTP-1B)是治疗糖尿病和肥胖症的一个潜在靶点。PTP-1B是胰岛素信号转导的主要负调控因子，II型糖尿病患者和糖尿病小鼠动物模型PTP-1B的表达水平和活性均明显提高，PTP-1B基因敲除小鼠具有正常表型且表现出显著增强的胰岛素敏感性。毛地黄鼠尾草的甲醇提取物有良好的PTP-1B抑制活性。本项目采用活性跟踪的方法对毛地黄鼠尾草进行系统的次生代谢物研究，找到该植物中具有抑制PTP-1B作用的单体化合物，对含量高的天然活性化合物进行结构优化，通过构效关系的研究，设计优化出具有更好的抑制PTP-1B作用的先导化合物；结合PTP-1B结构的特点及其去磷酸化的作用机制，探讨活性化合物的抑制作用是否是可逆的及活性化合物是否是竞争性抑制剂，为II型糖尿病及肥胖症的治疗奠定理论基础。

Protein tyrosine phosphatase 1B (PTP-1B) acts as a negative regulator of insulin signaling, and selective inhibition of PTP-1B has served as a potential drug target for the treatment of type II diabetes and obesity. The protein levels are increased in insulin-resistant diabetes patients and the PTP-1B gene knock-out mice has shown increasing insulin sensitivity.The methanol extracts of S. digitaloides showed significant inhibitory activities against PTP-1B. This project aimed at screening for PTP-1B inhibitors from S. digitaloides using bioassay-guided fraction and purification.The inhibition mechanism will be studied to get the site of action. And the structure-activity relationship and structural optimization of the active compounds will be studied to get lead compounds for type II diabetes and obesity. This study will establish the theoretical basis for the treatment of type II diabetes and obesity.