靶向诱导蛋白质降解是调控细胞内非酶蛋白的重要方法。靶向诱导蛋白降解缀合物借助泛素E3连接酶实现对特定蛋白的泛素化并降解，直接下调细胞内特定蛋白含量。本研究围绕靶向诱导蛋白降解缀合物研究中的两个难点问题：如何发现可用于该系统的泛素E3连接酶和如何基于泛素E3连接酶设计靶向诱导蛋白降解缀合物，针对前期已深入研究的泛素化E3连接酶Keap1开展工作，主要目标是基于Keap1设计和发现靶向诱导tau蛋白降解缀合物。主要思路是通过分析较强的Keap1结合配体和tau蛋白识别配体的结构特征，设计并合成合理组装的具有双功能单元可诱导tau蛋白降解的缀合物，进而对所设计合成得到的缀合物进行E3连接酶结合、目的蛋白结合、目的蛋白泛素化和降解等多层次评价，阐明该缀合物通过E3泛素连接酶Keap1对tau蛋白进行泛素化并诱导降解的机制，并探索此类化合物在体外和体内的阿尔兹海默病模型中的治疗效果。

Induced protein degradation by PROTACs (Proteolysis Targeting Chimeras) is an emerging way to target non-enzymic targets. PROTACs can selectively ubiquitinate interest proteins, leading to subsequent proteasome-mediated degradation. In this project, we focus on the two main hurdles in the research of PROTACs: the discovery of available E3 ligase and the design methods of PROTACs for specific E3 ligase. We plan to explore the possibility of ubiquitin E3 ligase Keap1 in design of PROTACs and discover Keap1-based PROTACs to degrade tau. The Keap1 ligand and tau ligand information will be incorporated into the design of PROTACs, and the synthesized PROTACs will be texted for the binding affinity with E3 ligase Keap1 and protein of interest tau, the induced tau degradation effects and the detailed tau downregulation mechanism. The optimized PROTACs will be further investigated in the cellular and in vivo models of Alzheimer's disease to explore the therapeutic applications of induced tau degradation.