International Journal of Molecular Medical Science, 2024, Vol.14, No.1, 56-60 http://medscipublisher.com/index.php/ijmms 59 Figure 4 X-ray crystal structures of SARS-CoV-2 PLpro with biarylphenyl PLpro inhibitors 2 Analysis of Research Findings In this study, the research team made a breakthrough confirmation that the papain-like protease (PLpro) of SARS-CoV-2 is an effective drug target. Through detailed structural analysis, they discovered the Val70Ub site on PLpro for the first time, suggesting its potential as a drug-binding site. This discovery provides a foundation for designing novel antiviral drugs. Using a structure-guided approach, the team successfully developed a series of non-covalent PLpro inhibitors targeting this new site. Among these inhibitors, Jun12682 was particularly noted for its exceptional efficacy. It not only demonstrated potent PLpro inhibitory activity in vitro but also proved to effectively inhibit SARS-CoV-2 replication in a mouse model, showing its great potential as a therapeutic drug. The discovery of Jun12682 validates the strategy of effectively blocking SARS-CoV-2 replication by targeting the Val70Ub site on PLpro, and it opens new directions for future drug development against SARS-CoV-2 and potential variants of coronaviruses. This breakthrough holds significant importance for current COVID-19 treatment research and offers new insights and strategies for the global scientific community in exploring more effective methods for viral treatment. 3 Evaluation of the Research This study, by integrating advanced methods from structural biology and medicinal chemistry, successfully identified Jun12682 as a potential drug candidate against the SARS-CoV-2 virus, demonstrating the research team's exceptional capability in scientific innovation. Through precise analysis of the structure and function of the PLpro enzyme, the research not only deepened our understanding of viral biology but also showed how to translate complex scientific knowledge into practical therapeutic strategies. The discovery of Jun12682 validates the feasibility, both theoretically and practically, of therapies targeting the SARS-CoV-2 PLpro enzyme, offering new hope and possibilities for combating the current pandemic and potential future coronavirus variants. 4 Conclusions Jun12682, as a novel PLpro inhibitor, has shown significant anti-SARS-CoV-2 activity both in vitro and in vivo, offering not only a new potential means to combat the COVID-19 pandemic but also new directions and strategies for the development of therapeutic drugs for coronavirus diseases. This work highlights the importance of PLpro as a drug target and demonstrates the power of structure-guided design methods in modern drug discovery.
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