Investigation of Antiviral Activities from Natural Compounds against SARS-CoV-2 Infection

Human coronaviruses (HCoVs) have been recognized as newly emerged viruses linked to severe diseases, particularly due to urbanization and increased interactions with wildlife in wet markets, which facilitate species crossovers. SARS-CoV-2 remains a concern despite vaccination efforts, driven by the emergence of variants that evade immune responses through mutations in the spike protein, which is essential for viral entry and pathogenicity. These mutations can enhance the virus’s ability to bind to host cells and evade immune detection, highlighting the S protein as a potential target for antiviral drug development. In this study, we tested three compounds and identified Punicalagin as a notable inhibitor of SARS-CoV-2 entry. While Punicalagin is recognized for its ability to inhibit viral replication by targeting 3CLpro and nsp13 helicase, its specific mechanism of action during viral entry remains under investigation. This study evaluates Punicalagin’s inhibitory activity on the viral entry of wild-type and variant strains in vitro, aiming to elucidate its target, whether the S protein or other essential proteases fundamental for spike activation, and clarify at which stage of viral entry this compound exerts its effects. Overall, our investigation clarifies that Punicalagin inhibits SARS-CoV-2 through a multi-target approach, not just at the entry point.