可控性蛋白降解靶向嵌合体(PROTACs)技术研究进展  

Research progress in controllable proteolysis targeting chimeras

作　　者：牟伊 文帅 王燕 姜正羽 MOU Yi;WEN Shuai;WANG Yan;JIANG Zheng-yu(College of Pharmacy and Chemistry&Chemical Engineering,Taizhou University,Taizhou 225300,China;Jiangsu Key Laboratory of Drug Design and Optimization,School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]泰州学院医药与化学化工学院,江苏泰州225300 [2]中国药科大学药学院,江苏省药物分子设计与成药性优化重点实验室,江苏南京210009

出　　处：《药学学报》2023年第8期2193-2202,共10页Acta Pharmaceutica Sinica

基　　金：江苏省高校自然科学基金(21KJB350008);泰州市社会发展项目(TN202135);江苏省“六大人才高峰”资助(YY-110).

摘　　要：蛋白降解靶向嵌合体(PROTACs)是一类新型蛋白降解技术,能同时结合E3连接酶与疾病相关蛋白,利用内源性泛素-蛋白酶体系降解靶蛋白。PROTACs具有较佳的通用性、较强的蛋白降解活性和较好的目的蛋白选择性,成为靶向蛋白降解领域的热点技术,但具有降解不受控的风险。可控PROTACs引入了特定的刺激响应触发元件,在特定的响应条件下可被触发,产生/终止后续的蛋白质降解效应。本文概述了可控PROTACs设计策略,并按照相应机制不同对代表化合物和研究进展进行了介绍,从而为可控PROTACs的研究提供借鉴和思路。Proteolysis targeting chimeras(PROTACs)is an innovative technique in targeted protein degradation.PROTACs is a heterobifunctional molecule which can bind to the E3 ligase and target protein to form a ubiquitination complex,resulting in the ubiquitin-proteasome system dependent degradation of target protein.PROTACs has been regarded as the promising method in drug discovery campaign,for its high commonality,potent degradation activity and unique selectivity profile.However,the catalytic mechanism also induces the uncontrollable protein degradation risk.Controllable PROTACs contain the responsive element in the molecular entity.In certain conditions,the element can be triggered to activate or terminate the degradation event.In this review,we will briefly summarize the strategies in controllable PROTACs and describe the representative examples according to the responsive mechanism.We hope this review could provide some insight into the further development of controllable PROTACs.

关 键 词：蛋白降解靶向嵌合体 靶向蛋白降解 可控性蛋白降解靶向嵌合体 

分 类 号：R914[医药卫生—药物化学]