Antiviral Efficacy of Lignan Derivatives (-)-Asarinin and Sesamin Against Foot-and-Mouth Disease Virus by Targeting RNA-Dependent RNA Polymerase (3Dpol)

Foot-and-mouth disease (FMD) is a highly contagious viral infection affecting livestock. Although inactivated vaccines are commonly used, their effectiveness is limited by an immunity gap. Therefore, complementary antiviral strategies are required for effective control and prevention. Lignans, plant-derived compounds, have shown promising antiviral properties, yet their potential against foot-and-mouth disease virus (FMDV) remains underexplored. This study employed virtual screening to identify lignan compounds targeting viral RNA-dependent RNA polymerase (3Dpol). Six lignan compounds were selected for cytotoxicity and antiviral activity evaluation including pre-viral entry, post-viral entry, and protective effect assays. Antiviral activity assay showed that (-)-asarinin and sesamin exhibit potent inhibition effects in the post-viral entry with EC50 of 15.11 μM and 52.98 μM, respectively, using immunoperoxidase monolayer assay. Both compounds exhibited dose-dependent reduction in viral replication with significant suppression of negative-strand RNA production. Lignans’ ability to target FMDV 3Dpol was further confirmed using a cell-based FMDV minigenome assay. Among the tested lignans, (-)-asarinin demonstrated remarkable inhibition of GFP expression (IC50 value at 10.37 μM), while sesamin required a higher concentration for similar effects. In silico prediction revealed that these lignans preferentially bind to FMDV 3Dpol active site. These findings are the first to establish (-)-asarinin and sesamin as promising antiviral candidates against FMDV.