The antiviral effect of TRPV1 antagonist SB-705498 against GCRV infection via inflammation and apoptosis inhibition.

Grass carp reovirus (GCRV), the causative agent of grass carp hemorrhagic disease (GCHD), inflicts substantial economic losses in aquaculture, yet effective therapeutic interventions remain limited. Previous studies have demonstrated that the host factor CiTRPV1 facilitates GCRV infection by activating multiple pro-viral signaling pathways, underscoring its potential as an antiviral target. Here, we screened a library of TRPV1-targeting small molecules and identified three candidates with significant antiviral activity in Ctenopharyngodon idella kidney (CIK) cells. Based on its favorable selectivity index, previously reported safety data in mammalian studies, SB-705498 was selected for further evaluation. This reported TRPV1 antagonist potently suppressed GCRV replication in CIK cells, exhibiting a half-maximal inhibitory concentration (IC50) of 9.536 nM, and markedly alleviated virus-induced cytopathic effects (CPE). Mechanistic analyses suggested that SB-705498 mainly acts during the early stage of GCRV infection and suppresses capsaicin-induced TRPV1-associated Ca2+ signaling, while also attenuating virus-triggered inflammatory responses and apoptosis. In an infection model using rare minnows (Gobiocypris rarus), administration of SB-705498 significantly enhanced host survival and substantially reduced the relative abundance of GCRV VP4 RNA in key tissues, including the brain, gills, and skin. Together, these results identify SB-705498 as a promising anti-GCRV lead compound, providing a compelling rationale for developing host-directed antiviral therapeutics against GCHD.