Research progress of proteolytic targeting chimera in anti-pathogen drug development
[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.
proteolysis-targeting chimerainfectious diseasedrug research and developmentantiviral drugantibacterial drug
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