靶向蛋白降解技术的开发之路  

Advances in targeted protein degradation

作　　者：王蔚 盛春泉 WANG Wei;SHENG Chunquan(Department of Medicinal Chemistry,School of Pharmacy,Naval Medical University(Second Military Medical University),Shanghai 200433,China)

机构地区：[1]海军军医大学(第二军医大学)药学系药物化学教研室,上海200433

出　　处：《海军军医大学学报》2024年第6期671-679,共9页Academic Journal of Naval Medical University

基　　金：国家自然科学基金青年科学基金(82204211).

摘　　要：靶向蛋白降解是当前热门的化学敲除工具和新药研发策略。与传统小分子抑制剂相比,靶向蛋白降解技术利用机体固有的蛋白清除机制(如泛素-蛋白酶体系统或溶酶体途径)特异性降解致病目标蛋白,在降低药物毒性和不良反应、克服耐药及靶向“难成药”靶点等方面具有突出优势。本文结合笔者团队的相关研究,聚焦多种新兴的靶向蛋白降解技术,如蛋白水解靶向嵌合体、分子胶、溶酶体靶向嵌合体、自噬体绑定化合物、自噬靶向嵌合体等,分析靶向蛋白降解技术的应用前景和未来发展趋势。Targeted protein degradation(TPD)is emerging as a promising strategy for chemical knockdown and drug discovery.TPD strategies eliminate disease-associated proteins by hijacking the intracellular proteolysis machinery,including the ubiquitin-proteasome system or the lysosomal pathway.Compared to traditional small-molecular inhibitors,TPD strategies exhibited significant advantages in reducing toxic side effects and the risk of drug resistance,and expanding the target space to“undruggable”proteins.Inspired by our research findings in the field of TPD,this review aims to summarize recent advances of major TPD technologies,e.g.,proteolysis targeting chimaera,molecular glue,lysosome-targeting chimaera,autophagosome-tethering compound,autophagy-targeting chimera,and discuss their potential applications and developing trend.

关 键 词：靶向蛋白降解 泛素-蛋白酶体系统 溶酶体途径 蛋白水解靶向嵌合体 新药研发 

分 类 号：R914[医药卫生—药物化学]