蛋白降解靶向嵌合体在小分子药物研发中的机遇与挑战  

Opportunities and Challenges of PROTAC in R&D of Small-molecule Drugs

作　　者：曾申昕 黄文海[1] 沈正荣 ZENG Shenxin;HUANG Wenhai;SHEN Zhengrong(Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province,Hangzhou Medical College,Hangzhou 310013,China)

机构地区：[1]杭州医学院浙江省神经精神疾病药物研究重点实验室,浙江杭州310013

出　　处：《药学进展》2020年第11期801-816,共16页Progress in Pharmaceutical Sciences

基　　金：浙江省神经精神疾病药物研究重点实验室资助(No.2019E10021);国家卫生健康委科学研究基金——浙江省医药卫生重大科技计划(省部共建)重点项目(No.WJKZJ-1918);浙江省医学科学院青年基金(No.C11905Q-04)。

摘　　要：蛋白降解靶向嵌合体(PROTAC)技术是一种通过泛素-蛋白酶体途径化学诱导靶蛋白降解的新兴策略。PROTAC是由靶蛋白配体和E3泛素连接酶配体通过适当的连接链连接而成的双功能分子,能够同时招募靶蛋白和E3泛素连接酶,从而诱导靶蛋白泛素化降解,具有广泛的应用前景和发展空间。主要简述小分子PROTAC的降解机制、发展历程,以及在药物研发中面临的机遇与挑战。Proteolytic targeting chimera(PROTAC)technique is an newly-emerging strategy to chemically induce the target protein degradation by the ubiquitin-proteasome pathway.PROTAC is a bifunctional molecule that consists of a target protein ligand,a linker and an E3 ligase ligand,which can simultaneously recruit target protein and E3 ligase,ultimately leading to the target protein degradation.The promising application and development of PROTAC has been rapidly gaining the momentum in the field of drug discovery.The present review gives an overview of PROTAC,with respect to the mechanism of action,development history,as well as the opportunities and challenges in the discovery of small-molecule drugs.

关 键 词：蛋白降解靶向嵌合体 泛素-蛋白酶体系统 双功能分子 多聚泛素化 

分 类 号：R918[医药卫生—药学]