新型E3泛素连接酶配体开发方法的研究进展

Advances in the development of novel E3 ubiquitin ligase ligands

泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)负责正常和病理状态下的蛋白质降解,其中,E3连接酶可以选择性地将泛素连接到特定底物,对调节细胞稳态至关重要,其功能与癌症、心血管疾病等多种疾病相关。E3配体的发现有助于调控E3连接酶从而拓展疾病治疗的新思路。与此同时,近几年兴起的靶向蛋白降解(targeted protein degradation,TPD)药物尤其是蛋白水解靶向嵌合体(proteolysis targeting chimera,PROTAC)对E3配体有着相当大的依赖。本文对E3配体的发现技术包括基于活性的蛋白质图谱、基于片段的药物发现、基于文库的方法进行了综述,并简要介绍了配体发现技术中所涉及的蛋白质相互作用检测技术,希望为未来E3配体的发现以及疾病的治疗提供一定的思路。

The ubiquitin-proteasome system(UPS)is responsible for protein degradation in both normal and pathological states.E3 ligases selectively attach ubiquitin to specific substrates,which is essential for regulating cellular homeostasis.The function of E3 ligases has been associated with a variety of diseases,such as cancer and cardiovascular disease.The discovery of E3 ligands can help regulate E3 ligases,thus expanding new ideas for disease treatment.Targeted protein degradation(TPD)drugs,including proteolysis targeting chimera(PROTAC),have become increasingly popular in recent years due to their dependence on E3 ligands.In this paper,we review the discovery techniques of E3 ligands,including activity-based protein mapping,fragment-based drug discovery,and library-based methods,and briefly introduce the protein interaction detection techniques involved in the ligand discovery techniques,in the hope of providing certain ideas for the future discovery of E3 ligands as well as the treatment of diseases.