调控蛋白成熟与翻译后修饰的小分子设计策略  

Targeting protein folding and post-translational modifications by small molecules:review and prospects

作　　者：何彦仪 尤启冬[1,2] 王磊[1,2] HE Yan-yi;YOU Qi-dong;WANG Lei(Jiangsu Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 210009,China;School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学,江苏省药物分子设计与成药性优化重点实验室,江苏南京210009 [2]中国药科大学药学院,江苏南京210009

出　　处：《药学学报》2024年第11期2897-2911,共15页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82003582);江苏省自然科学基金-优秀青年基金(BK20230103)。

摘　　要：蛋白成熟与翻译后修饰是各类蛋白质发挥生物学功能的前提,在体内由多种复杂的生物系统协同调控,其中包括分子伴侣系统、泛素化系统、磷酸化系统和乙酰化系统等。合理调控上述系统可以实现对蛋白成熟和翻译后修饰过程的有效干预,逐渐成为有效的药物设计方向。本文回顾了调控蛋白成熟和翻译后修饰相关的分子设计策略,重点聚焦于靶向分子伴侣系统的小分子调控剂和异双功能分子策略。一方面基于分子伴侣系统调控蛋白成熟的生物学原理,总结靶向分子伴侣系统的小分子研发历程;另一方面围绕异双功能分子的设计原理和特点,归纳其在调控翻译后修饰中的应用和发展,为调控蛋白成熟与翻译后修饰过程的小分子设计提供新思路。Folding and post-translational modification of proteins are vital for their proper functionality,with various functional regulatory systems playing significant roles,including molecular chaperone systems,ubiquitination systems,phosphorylation systems,acetylation systems,etc.Precise regulations of these systems have emerged as an important trend in drug development.This review systematically summarizes the molecular control strategies related to protein folding and post-translational modification,with a specific focus on the molecular chaperone system and the strategy of heterobifunctional molecules.On one hand,based on the similarities and differences in molecular mechanisms and design strategies,we summarize the drug development process targeting the molecular chaperone system.On the other hand,we discuss the design principles and characteristics of dual-functional molecules,and summarize their applications and developments in the precise control of post-translational modifications,aiming to provide new insights for future design.

关 键 词：蛋白成熟 翻译后修饰 分子伴侣系统 异双功能分子 分子药物设计 

分 类 号：R914[医药卫生—药物化学]