靶向蛋白质降解的新兴技术及其研究进展

Research advances in new technologies in targeted protein degradation

靶向蛋白质降解技术是近十年来迅速发展起来的一项干扰蛋白质功能的重要技术。目前该领域发展最为成熟的是基于泛素化-蛋白酶体系统的蛋白水解靶向嵌合体(proteolysis-targeting chimera,PROTAC)技术。随着降解机制和降解对象的拓展,近几年相继涌现出各类新型靶向蛋白质降解技术,包括溶酶体靶向嵌合体(lysosometargeting chimera,LYTAC)技术、自噬靶向嵌合体(autophagy-targeting chimera,AUTAC)技术、自噬小体绑定化合物(autophagosome-tethering compound,ATTEC)技术以及分子伴侣介导的自噬(chaperone-mediated autophagy,CMA)嵌合体技术。新兴的靶向蛋白质降解技术探索真核细胞内的另一重要蛋白质降解体系——溶酶体降解系统,如内吞-溶酶体途径和自噬-溶酶体途径。本综述从各类蛋白质降解系统出发,总结各类蛋白质降解技术的作用机制和特点,重点介绍几类新兴技术的研究现状、优势和存在的问题。

In recent years,the targeted protein degradation technology has developed quickly,with proteolysistargeting chimera(PROTAC)as the best-known strategy through exploring the ubiquitin-proteasome system.A number of new targeted protein degradation strategies have been emerging to expand the scope of protein degradation technology,including lysosome-targeting chimeras(LYTACs),autophagy-targeting chimeras(AUTACs),autophagosome-tethering compounds(ATTECs)and chimeras based on chaperone-mediated autophagy(CMA).The emerging methodologies have explored another important protein degradation system in eukaryotes-lysosomal systems,such as the endosome-lysosome pathway and the autophagy-lysosome pathway.This review summaries the mechanisms and features of different strategies for targeted protein degradation,with a special emphasis on the new targeted protein degradation technologies,such as their current status,advantages and limitations.