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蛋白水解靶向嵌合体在抗病原体药物研发中的研究进展

Research progress of proteolytic targeting chimera in anti-pathogen drug development
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摘要 [背景]靶向蛋白降解技术依赖细胞内天然存在泛素化-蛋白酶系统与溶酶体降解系统两种方式,能够特异性地靶向癌症目标蛋白并对其进行降解,从而达到治疗疾病的目的,并已被证明可用于传统小分子难以靶向的不可成药受体蛋白.蛋白水解靶向嵌合体(PROTAC)作为一种较为成熟的靶向蛋白降解的双功能分子,多用于靶向癌症治疗,也进一步展现出在感染性疾病(抗病毒和抗菌)领域的优势,是利用细胞自身破坏机制降解特定疾病相关蛋白的最有前景方法之一.[进展]本文主要阐述PROTAC的分子组成和作用机制,分别介绍小分子形式和非小分子形式PROTAC的分类及其优势,并总结PROTAC在抗病毒感染(流感病毒、肝炎病毒、新型冠状病毒及人巨细胞病毒)和抗菌感染(结核分枝杆菌)方面的最新研究进展.[展望]考虑到PROTAC本身固有的缺点,可借助纳米颗粒等递送系统作为载体,从而改善其生物相容性和细胞渗透性,进而提高其靶向和治疗效果,旨在为更多PROTAC相关的药物研究提供思路. [Objective]The burgeoning issue of drug-resistant bacteria,accelerated by the excessive and inappropriate use of broad-spectrum antibiotics,has emerged as a major global health concern.The inefficacy of traditional small-molecule inhibitors,primarily due to their reduced specificity for viral target proteins and pronounced off-target effects,has significantly compromised their therapeutic utility.This situation underscores the critical need for novel and more effective anti-infective strategies.One such pioneering approach is the targeted protein degradation technology,which leverages two innate cellular pathways:the ubiquitin-proteasome and lysosomal degradation systems.It uniquely targets and degrades cancer-specific proteins,offering a groundbreaking therapeutic strategy.Notably,this method has shown efficacy against targets that are typically resistant to conventional small molecule drugs,including those previously considered"undruggable".Proteolysis-targeting chimera(PROTAC),a sophisticated form of bifunctional molecules in this realm,engage simultaneously with the target protein and a specific E3 ligase through their unique ligands.This interaction forms a tripartite complex of target protein-PROTAC-E3 ligase,which is instrumental not only in cancer therapy but also increasingly recognized in treating infectious diseases,including antiviral and antibacterial applications.PROTAC represents one of the most promising strategies for exploiting cellular degradation mechanisms to eliminate disease-related proteins.[Progress]In this review,we explore the composition,and mechanism of action of PROTAC.Different from the traditional small molecule inhibitors that block protein function,PROTAC achieves targeted therapeutics through an"occupation-driven"strategy,which entails the complete degradation of target proteins,thereby nullifying all their functions in an"event-driven"fashion.Crucially,this strategy does not require a high affinity between the PROTAC and the target protein.PROTAC molecules play a catalyst-like
作者 侍倩倩 倪秀冶 沈之阳 贾舒冰 刘培飞 陈洪敏 SHI Qianqian;NI Xiuye;SHEN Zhiyang;JIA Shubing;LIU Peifei;CHEN Hongmin(State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,School of Public Health,Xiamen University,Xiamen 361102,China)
出处 《厦门大学学报(自然科学版)》 CAS CSCD 北大核心 2024年第3期454-466,共13页 Journal of Xiamen University:Natural Science
基金 国家自然科学基金(82172007,81771977) 福建省杰出青年科学基金(2021J06007)。
关键词 蛋白水解靶向嵌合体 感染性疾病 药物研发 抗病毒药物 抗菌药物 proteolysis-targeting chimera infectious disease drug research and development antiviral drug antibacterial drug
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