膜蛋白及胞外蛋白靶向降解策略研究进展  

Research advances in targeted degradation strategies of membrane and extracellular proteins

作　　者：郭禹 段海婷 宋毅 车金鑫 雷涛[2] 董晓武 GUO Yu;DUAN Hai-ting;SONG Yi;CHE Jin-xin;LEI Tao;DONG Xiao-wu(Institute of Drug Discovery and Design,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China;Zhejiang Cancer Hospital,Hangzhou 310022,China)

机构地区：[1]浙江大学药学院药物发现与设计研究所,浙江杭州310058 [2]浙江省肿瘤医院,浙江杭州310022

出　　处：《中国药物化学杂志》2023年第10期721-735,共15页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(82173660);浙江省自然科学基金项目(LR21H300003);浙江省重点研发计划项目(2023C03111)。

摘　　要：靶向蛋白降解(targeted protein degradation,TPD)是一项具有前景的蛋白质稳态调控技术。在过去的二十年中,各种通过细胞内机制来降解具有挑战性的可溶性蛋白的技术得到了迅速发展,其中最具代表性的是基于泛素化-蛋白酶体系统的蛋白水解靶向嵌合体(proteolysis-targeting chimera,PROTAC)技术。尽管以PROTAC为代表的TPD展现出广阔的治疗潜力,但这些TPD技术大多无法作用于在蛋白质组中同样重要的胞外蛋白及膜蛋白。随着近几年对蛋白降解途径的进一步拓展与应用,对于胞外蛋白及膜蛋白的干预技术不断涌现。本文作者将对目前已报道的膜蛋白及胞外蛋白靶向降解策略的作用机制和特点进行综述,并介绍几类新兴技术的研究进展、优势和不足,以期为膜蛋白稳态调控策略的进一步发展提供参考。Targeted protein degradation(TPD)is a promising technique for regulating protein homeostasis.Over the past two decades,technologies relying on various intracellular mechanisms to degrade challenging cytosolic targets have developed rapidly,the most representative of which is the proteolysis-targeting chimera(PROTAC)technology based on the ubiquitination-proteasome system.Although TPDs represented by PROTAC show broad therapeutic potential,most TPD technologies cannot act on extracellular and membrane proteins that are equally important in the proteome.With the further expansion and application of protein degradation pathways in recent years,intervention technologies for extracellular and membrane proteins are emerging.This article will review the mechanisms and characteristics of the reported membrane and extracellular protein targeted degradation strategies,and introduce the development,advantages,and disadvantage of several emerging technologies,to provide a basis for the further development of membrane protein homeostasis regulation strategies.

关 键 词：靶向蛋白降解 膜蛋白及胞外蛋白 溶酶体靶向嵌合体 细胞因子受体靶向嵌合体 蛋白降解靶向抗体 

分 类 号：R914[医药卫生—药物化学]