蛋白降解靶向嵌合体技术在神经退行性疾病中的研究进展  

Progress in the research of targeted protein degraders based on PROTAC for Neurodegenerative diseases

作　　者：谢欣言 许玮淇 刘婷婷 周磊 XIE Xinyan;XU Weiqi;LIU Tingting;ZHOU Lei(School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou 510006,China)

机构地区：[1]广东药科大学药学院,广东广州510006

出　　处：《广东药科大学学报》2025年第2期139-148,共10页Journal of Guangdong Pharmaceutical University

基　　金：国家自然科学基金青年基金项目(82204968);2023年广东省级大学生创新训练项目(S202310573037);广州市科技计划项目(2023A04J1153)。

摘　　要：蛋白降解靶向嵌合体(proteolysis-targeting chimeras,PROTAC)技术通过泛素-蛋白酶体系统,使异双功能分子可以快速诱导靶蛋白多泛素化,进而实现靶蛋白的特异性降解。常见神经退行性疾病多因特定蛋白质的异常聚集,导致神经元死亡,从而引发一系列症状。由于这些特定蛋白具有“不可成药性”,传统的小分子药物无法有效结合相应靶点,目前的治疗手段仅能延缓病情进展,无法彻底根治疾病。PROTAC技术可以直接靶向并降解这些异常聚集的蛋白,因而有望成为根治神经退行性疾病的潜在手段。本文总结了基于PROTAC技术设计的神经退行性疾病相关的聚集蛋白降解剂,分析了该技术的优势与挑战,并探讨了PROTAC技术未来的发展方向,拟为神经退行性疾病的药物研发提供参考。Proteolysis-targeting chimeras(PROTAC)technology enables heterobifunctional molecules to rapidly induce polyubiquitination of target proteins through the ubiquitin-proteasome system,leading to specific degradation of target proteins.Common neurodegenerative diseases are caused by aberrant aggregation of specific proteins,leading to neuronal death and a series of symptoms.Due to the'undruggable'nature of these specific proteins,traditional small molecule drugs are unable to effectively bind to the corresponding targets,and current therapies can only slow down the progression of the disease,but not completely cure it.Therefore,there is an urgent need for a novel approach to treat neurodegenerative diseases,and PROTAC technology,which can directly target and degrade these abnormally aggregated proteins,is expected to be a potential treatment for neurodegenerative diseases.This paper summarised the design of aggregated protein degraders related to neurodegenerative diseases based on PROTAC technology,analyse the advantages and challenges of this technology,and discussed the future development of PROTAC technology.

关 键 词：神经退行性疾病 蛋白降解靶向嵌合体 蛋白降解剂 

分 类 号：R977.6[医药卫生—药品]