自发现至今，PTP1B一直被作为治疗2型糖尿病的潜在分子靶点，已有很多高效的PTP1B抑制剂被陆续报道，细胞实验也显示了积极的治疗前景。但是由于缺乏选择性，至今只有两个化合物进入临床阶段，且都因毒副作用而停止后续研究。选择性成为PTP1B抑制剂类抗糖尿病药物研发的瓶颈。. 本项目拟靶向识别位点Ala27，以天然产物为先导，利用基于结构的药物分子设计和计算机辅助分子设计，进行分子骨架构建和选择性基团的添加。采用实验室构建完成的PTP1B和TCPTP活性筛选模型，对设计合成的溴酚化合物进行活性筛选和选择性测定。研究所获得的高选择性PTP1B抑制剂对胰岛素靶向组织糖吸收的影响, 以及对胰岛素抵抗大鼠糖代谢和胰岛素敏感性的影响，并揭示其作用的分子机制。本研究将有助于全面认识PTP1B的结构与功能，对发展靶向PTP1B的抗2型糖尿病药物具有重要价值。

As a negative regulator in both insulin and leptin signaling, Protein tyrosine phosphatase 1B (PTP1B) has become a promising drug target for the treatment of type 2 diabetes and obesity since its discovery 27 years ago. Some efficient PTP1B inhibitors had been reported successively in the last decade. Howerver，only two PTP1B inhibitors had entered clinical research and were stopped further development due to their toxic and side effects. Selectivity has become one of the most challenging aspects for PTP1B inhibitors as anti-diabetic drugs.. Based on active nature products, a serie of uncharged catechol derivatives were identified as PTP1B inhibitors by targeting Ala27 through structure-based strategy and computer-aided molecular design. Inhibitory acitvities and selectivities were identified by PTP1B and TCPTP inhibitory assay in our own laboratory. The influence and mechanism of selectivity PTP1B inhibitors on glucose absorption function of tissues and rats with insulin resistance were also studied. This study will contribute to a comprehensive understanding of the structure and function of PTP1B, which would be important for the development of anti-diabetic drugs targeted PTP1B.