靶向蛋白降解技术研究进展与展望  

Advances and prospects in targeted protein degradation

作　　者：周洛竹 盛春泉 ZHOU Luozhu;SHENG Chunquan(Department of Medicinal Chemistry,School of Pharmacy,Naval Medical University,Shanghai 200433,China)

机构地区：[1]海军军医大学药学系药物化学教研室,上海200433

出　　处：《药学实践与服务》2023年第6期341-351,365,共12页Journal of Pharmaceutical Practice and Service

摘　　要：靶向蛋白降解技术(TPD)通过调动细胞内固有的两大蛋白降解机制——泛素-蛋白酶体系统(UPS)或溶酶体途径下调致病靶蛋白,有望克服传统抑制剂的局限性,挑战“难成药”靶点,为药物开发提供新的靶向治疗手段。重点关注多种有前景的靶向蛋白降解技术,包括蛋白水解靶向嵌合体(PROTAC)、分子胶、溶酶体靶向嵌合体(LYTAC)、自噬体绑定化合物(ATTEC)、自噬靶向嵌合体AUTAC和AUTOTAC,分析代表性的案例及其潜在的应用与挑战。Targeted protein degradation(TPD)techniques eliminate pathogenic proteins by hijacking the intracellular proteolysis machinery which includes the ubiquitin-proteasome system(UPS)and the lysosomal degradation pathway,holding promise to overcome the limitations of traditional inhibitors and further broaden the target space including many“undruggable”targets,and provide new targeted treatments for drug discovery.In this review,recent advances in a variety of promising TPD strategies were summarized,such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting chimaera(LYTAC),autophagosome-tethering compound(ATTEC),autophagy-targeting chimera AUTAC and AUTOTAC,particularly.The representative case studies,potential applications and challenges were analyzed.

关 键 词：靶向蛋白降解 泛素-蛋白酶体系统 溶酶体途径 药物发现 PROTAC 

分 类 号：R341[医药卫生—基础医学]