Brequinar inhibits enterovirus replication by targeting biosynthesis pathway of pyrimidines

Infection of human enteroviruses could cause diverse diseases ranging from mild respiratory symptoms to neurological complications, and even death. Currently, no-FDA approved antiviral drug is available for clinical treatment of human enteroviruses infection. Brequinar is an immunosuppressive drug currently being used for the prevention of organ graft rejection. The drug repurposing studies show that Brequinar exhibits potent antiviral activity against diverse viruses, including flaviviruses, alphavirus, rhabdovirus, and influenza viruses. The antiviral effect of Brequinar on human enterovirus infection has not been investigated yet. Here, the in vitro study shows that Brequinar potently inhibited EV71, EV70, and CVB3 replication at 50% inhibitory concentration (IC50) of 82.40 nM, 29.26 nM, and 35.14 nM, respectively. The antiviral activity of Brequinar was reversed by supplement exogenous pyrimidines, indicating that the antiviral effect of Brequinar against enterovirus relies on the inhibition of dihydroorotate dehydrogenase (DHODH) activity, which is responsible for the de novo biosynthesis of pyrimidines. These data extend the antiviral spectrum of Brequinar and indicate that Brequinar could serve as a promising antiviral drug to treat EV71 and other enterovirus infections.