摘要
蛋白降解嵌合体(proteolysis targeting chimeras,PROTACs)是一类具有募集靶蛋白并诱导其泛素化降解的双功能分子。相较于传统小分子抑制剂,PROTACs这种直接降解目标蛋白的作用模式具有高选择性,高效性,更重要的是该技术可以靶向不可成药蛋白,解决小分子药物耐药性问题等优势。E3泛素连接酶参与泛素蛋白酶体系统降解途径,决定PROTACs分子靶向E3泛素连接酶部分的特异性识别,庞大的E3家族对PROTACs技术的发展至关重要。第二代小分子类PROTACs相较于第一代多肽类PROTACs分子具有良好的跨膜性,稳定性及成药性。本文主要基于E3泛素连接酶小分子配体设计的PRO-TACs分子的作用机制、最新研究成果、以及目前存在的问题进行论述。
Proteolysis targeting chimeras(PROTACs)is a class of bifunctional molecules that recruit target proteins and induce their ubiquitination and degradation.Compared with traditional small molecule inhibitors,the mode of action of PROTACs that directly degrades the target protein has high selectivity and efficiency.More importantly,the technology can target non-druggable proteins and solve the problems of small molecule drug resistance.E3 ubiquitin ligase participates in the degradation pathway of the ubiquitin proteasome system,and determines the specific recognition of the PROTACs molecule targeting E3 ubiquitin ligase.The huge E3 family is crucial to the development of PROTACs technology.Compared with the first-generation peptide PROTACs,the second-generation small molecule PROTACs have better transmembrane properties,stability and druggability.This review mainly introduces the mechanism of action of PROTACs based on the design of small molecule E3 ligase,the latest research results,and the current problems.
作者
刘斌
朱周静
仝红娟
张彦民
唐初
LIU Bin;ZHU Zhou-jing;TONG Hong-juan;ZHANG Yan-min;TANG Chu(School of Pharmacy,Shaanxi Institute of International Trade and Commerce,Xianyang 712046,China;Collaborative Innovation Center of Green Manufacturing Technology for Traditional Chinese Medicine in Shaanxi Province,Xianyang 112046,China;School of Life Science and Technology,Xidian University,Xi'an 110126,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2022年第5期334-341,共8页
Chinese Pharmaceutical Journal
基金
陕西省自然科学基础研究计划项目资助(2021JM-540,2021JQ-885)
陕西国际商贸学院省级科研平台重点项目资助(2019XT205)
陕西省中药绿色制造技术协同创新中心重点培育项目资助(2019XT105)
陕西国际商贸学院“中药药效物质研究”创新团队资助项目资助(SSY18TD01)
关键词
E3泛素连接酶
小分子蛋白降解嵌合体
药物设计
E3 ubiquitin ligase
small molecule proteolysis targeting chimeras
drug design
作者简介
刘斌,男,博士,副教授,研究方向:药物分子设计合成,Tel:(029)33694369。
