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

[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 role in the whole process and are less prone to drug resistance,offering great potential in drug development and disease treatment.The versatility of PROTAC is further highlighted by their efficacy in both small and non-small molecule formats,including peptide,nucleic acid,and antibody modalities.In addition,the article highlights the latest advances in PROTAC-based drug development for infectious diseases.The article describes PROTAC in terms of both antiviral and antimicrobial infections.For antiviral applications,the focus is on influenza viruses(e.g.,live attenuated influenza A virus vaccine,pentacyclic triterpenoid PROTAC targeting the degradation of hemagglutinin,PROTAC targeting influenza virus neuraminidase),hepatitis virus(e.g.,PROTAC targeting the hepatitis C virus NS3/4A protease and PROTAC targeting the hepatitis B virus oncogenic X protein)and SARS-CoV-2 virus(e.g.,Pan-coronavirus antiviral drugs based on indomethacin,PROTAC targeting the main coronavirus protease).Additionally,PROTAC targeting the degradation of human cytomegalovirus cell cycle protein-dependent kinase is also discussed,highlighting the breadth of PROTAC application in viral infections.While PROTAC technology is still in its infancy in antimicrobial infections,a novel PROTAC based on the casein hydrolytic protease proteolysis(ClpCP)mechanism(BacPROTAC)has shown breakthrough results,mainly in Mycobacterium tuberculosis,with potential future applications to other bacterial species.[Perspective]However,despite these significant advances,PROTAC technology is not without its limitations.The high molecular mass and surface polarity of PROTAC can negatively impact their bioavailability and cellular permeability.Additionally,challenges such as weak specificity and the"hook effect"can affect the targeting efficiency of these molecules.To address these issues,the paper proposes the combination of PROTAC molecules with nanoparticles.This combination aims to promote the selective localization of PROTAC to tumor tissues,thus overcoming their poor water solubility and limited cellular permeability.This approach enables the precise delivery of degradant molecules with enhanced targeting and cell permeability,utilizing both passive and active targeting strategies.Furthermore,exploring novel ligands for E3 ligases presents a daunting yet essential task in expanding the scope of PROTAC technology.While PROTAC is primarily advanced for cancer therapy,its application in targeted protein degradation in bacteria and viruses is still in a nascent stage.The development of chemically induced knockdown of pathogenic proteins,antiviral PROTAC,or BacPROTACs is poised to open new avenues in next-generation antimicrobial therapeutics.In conclusion,this review aims to ignite new ideas and foster further research in the rapidly evolving field of PROTAC-related drug discovery.The potential of PROTAC to revolutionize the treatment of various diseases,particularly in the context of drug-resistant infections and previously"undruggable"targets,underscores their significance in modern medicine.