靶向特定氨基酸的共价抑制剂研究进展  

Research Progress of Covalent Inhibitor Targeting Specific Amino Acid

作　　者：王傲雪 裴俊平 王贯 欧阳亮[1] WANG Aoxue;PEI Junping;WANG Guan;OUYANG Liang(State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu 610041,China)

机构地区：[1]四川大学华西医院生物治疗国家重点实验室,四川成都610041

出　　处：《药学进展》2022年第1期33-46,共14页Progress in Pharmaceutical Sciences

基　　金：国家自然科学基金项目(No.81922064,No.22177083,No.81874290)。

摘　　要：共价抑制剂通过共价键与靶蛋白结合并对其产生抑制作用。虽然在很长一段时间内因为潜在的脱靶可能性使研究者们望而却步,但随着近年来对共价抑制剂作用机制、亲电弹头与亲核氨基酸性质的深入研究与探索以及有效开发策略的提出与改进,众多共价抑制剂成功上市。其在疾病治疗中的优势也逐渐显现,这使得共价抑制剂成为药物研发的热点。通过对共价抑制剂的结合机制、研究进展、开发策略、优势与挑战进行综述,并对其发展前景与方向进行讨论,以期为新型共价抑制剂的开发提供参考。Covalent inhibitors bind to target proteins through covalent bonds, and further inhibit them. Researchers have been discouraged by covalent inhibitors because of their potential long-term off-target effect. However, with the in-depth study and exploration of the mechanism of covalent inhibitors, the character of electrophilic warhead and nucleophilic amino acids as well as the implementation and improvement of effective development strategies in recent years, many covalent inhibitors have been successfully approved. Their advantages in the treatment of diseases have gradually emerged, making covalent inhibitors a hot spot in drug development. This review focuses on the binding mechanism,research progress, development strategies, advantages and challenges of covalent inhibitors, and discusses their development prospect and direction, in the hope of providing some reference for the development of novel covalent inhibitors.

关 键 词：共价抑制剂 亲电试剂 靶向亲核氨基酸残基 

分 类 号：R914[医药卫生—药物化学]