药学学报, 2021, 56(2): 445-455
引用本文:
沈心远, 吴诗慧, 李保林, 李徐诺, 吴昊姝, 曹戟. 蛋白水解靶向嵌合体(PROTAC)连接链优化的研究进展[J]. 药学学报, 2021, 56(2): 445-455.
SHENG Xin-yuan, WU Shi-hui, LI Bao-lin, LI Xu-nuo, WU Hao-shu, CAO Ji. Advances in the optimization of the linker in proteolysis-targeting chimeras (PROTAC)[J]. Acta Pharmaceutica Sinica, 2021, 56(2): 445-455.

蛋白水解靶向嵌合体(PROTAC)连接链优化的研究进展
沈心远, 吴诗慧, 李保林, 李徐诺, 吴昊姝, 曹戟
浙江大学药学院, 浙江 杭州 310058
摘要:
近年来,具有高度选择性和效能的靶向蛋白降解技术在药学中的潜在应用已逐步受到关注。其中,起到诱导靶蛋白降解作用的蛋白水解靶向嵌合体(proteolysis targeting chimeras,PROTAC)是近年来药物研发领域的新热点之一。目前,PROTAC的研究主要围绕理性合理设计PROTAC分子、发现新型E3泛素连接酶配体和提升PROCTAC分子成药性等方面,相关理论发展迅速。本文聚焦于PROTAC分子中的连接链部分,从连接链的长度、连接链与配体的结合位点以及连接链的化学结构三个角度总结了近年来连接链的差异如何影响E3酶-PROTAC-靶蛋白三元复合物生成的相关研究进展,并进一步讨论了连接链差异对于PROTAC分子的降解效率和选择性的影响。
关键词:    蛋白水解靶向嵌合体      连接链      E3酶-蛋白水解靶向嵌合体-靶蛋白三元复合物      蛋白降解效率      底物降解选择性     
Advances in the optimization of the linker in proteolysis-targeting chimeras (PROTAC)
SHENG Xin-yuan, WU Shi-hui, LI Bao-lin, LI Xu-nuo, WU Hao-shu, CAO Ji
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract:
With high selectivity and potency, target protein degradation technology has recently emerged as a strategy for drug discovery and design. Proteolysis-targeting chimeras (PROTAC) function as inducers for the degradation of target proteins and are a research focus in drug development. Current research on PROTAC mainly revolves around the rational design of PROTAC molecules, the discovery of new E3 ubiquitin ligase ligands and improvement in drug targeting. In this review, we focus on the PROTAC linker and its effects on the generation of the E3 enzyme-PROTAC-target protein ternary complex from three standpoints:length, binding site and chemical properties. We discuss the influences of the linker on the efficacy and the selectivity of PROTAC molecules.
Key words:    proteolysis targeting chimeras    linker    E3 enzyme-proteolysis targeting chimeras-protein of interest ternary complex    degradation efficacy    substrate selectivity   
收稿日期: 2020-07-31
DOI: 10.16438/j.0513-4870.2020-1272
基金项目: 国家自然科学基金资助项目(81872885);浙江省科学技术协会“育才工程”(2018YCGC002).
通讯作者: 曹戟,Tel:86-571-88208401,E-mail:caoji88@zju.edu.cn
Email: caoji88@zju.edu.cn
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