蛋白质降解靶向嵌合体的研究进展

Advances in Proteolysis Targeting Chimeras

近年来,蛋白质降解靶向嵌合体(proteolysis targeting chimeras,PROTACs)作为一种新型靶向治疗方式成为人们关注的焦点。PROTACs是一类双靶点嵌合体分子,由3个部分组成:靶向结合目标蛋白的配体、招募E3泛素连接酶的配体以及两者之间的连接链。它能将目标蛋白与E3泛素连接酶的距离拉近,利用细胞内固有的泛素-蛋白酶体系统选择性诱导目标蛋白降解。与传统的小分子抑制剂相比,PROTACs在药物的剂量、选择性、耐药性以及调节“不可成药靶点”等方面具有潜在优势,目前已开始从基础研究走向临床试验。笔者将结合最新的相关研究进展,总结PROTACs的优势、设计要素以及目前面临的主要问题等。

In recent years,proteolysis targeting chimeras(PROTACs)have emerged as a novel therapeutic modality in drug discovery and become the focus of great interest.PROTACs are bifunctional molecules consisting of a ligand targeting a POI(protein of interest),a ligand for recruiting an E3 ubiquitin ligase and a linker connecting these ligands.PROTACs are designed to bind both the target protein and the E3-ubiquitin ligase,therefore recruiting an E3 ubiquitin ligase to a specific target protein and thereby providing a mechanism to ubiquitinate and degrade specific pathological proteins by the proteasome.Compared with traditional small-molecule inhibitors,PROTACs have the potential advantages with respect to dosage,selectivity,drug resistance and modulating"undruggable"targets.Based on the latest research progress,this review summarizes the advantages of PROTACs,the elements of PROTACs design,and the current problems.