靶向蛋白质降解技术研究进展

靶向蛋白质降解技术可有效克服DNA敲除、RNA干扰等传统药物靶点确认及干扰策略的局限性。近年来,一系列新型靶向蛋白质降解技术不断涌现,在药物研发领域展现出极好的应用前景。本文综述了靶向蛋白质降解技术的最新研究进展,重点介绍各种技术的作用机制、应用情况、技术优势及目前存在问题,以期为药物靶点确认及新药开发提供有力理论及技术支持。

Research Progress of Targeted Protein Degradation Technology

Targeted protein degradation based on the“event driven”mode of action directly targets and catalyzes the degradation of the target protein.Compared with the traditional small molecule inhibitors based on the“occupation driven”mode of action,there is no need to be interact with the target protein for a long time and high intensity.Low concentration compounds can achieve the efficient degradation of the target protein with high activity,high selectivity,targeting undruggable proteins and many other advantages.In addition,targeted protein degradation also effectively overcomes the limitations of irreversibility,poor druggability and off-target effects of traditional drug target identification and interference strategies such as DNA knockout and RNA interference.In recent years,a series of new targeted protein degradation technologies have been developed,including deGradFP,PROTAC,molecular glue,dTAG,AID and Trim-Away based on the ubiquitin-proteasome system,specific ubiquitination the protein of interest by recruiting ubiquitin-protein ligases(E3)and subsequent degradation by the 26 S proteasome.The AUTAC and ATTEC technologies based on the autophagy pathway and the LYTAC technology based on the endosome-lysome pathway ultimately direct the target proteins to the lysosome for degradation.These strategies have successfully degraded a varitey of human disease-related proteins in vivo and in vitro,showing excellent prospects for drug design and development,especially many PROTAC drugs such as ARV-110 and ARV-471 have entered the clinical trial stage,showing good therapeutic effects in breast cancer,prostate cancer and other cancer diseases.This paper briefly introduces the research status of different targeted protein degradation technologies,systematically summarizes the advantages and disadvantages of each technology,and prospects the challenges faced by this technology in the field of drug research and development.