Ondansetron exhibits potent antiviral activity against enterovirus 71 infection in vitro and in vivo.

Enterovirus A71 (EV-A71) is a major causative agent of hand, foot, and mouth disease (HFMD) with neurotropism, and currently no approved antiviral therapies are available. In this study, we found that the ondansetron exhibits antiviral activity against EV-A71 infection. Ondansetron significantly reducing viral RNA levels, progeny virus production, and VP1 protein expression in a dose-dependent manner. In vivo, ondansetron treatment increased survival of neonatal mice and decreased viral loads in multiple tissues. Mechanistically, ondansetron modulates cholesterol metabolism-related genes to affect cell cholesterol stability and interferes with viral attachment during the early stage of infection, thereby inhibiting EV-A71 infection. These findings indicate that ondansetron is a promising candidate for drug repurposing to treat EV-A71 infection.