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Over the years, the hand, foot and mouth disease (HFMD) has sparked epidemics across many countries which mainly affected young children. While symptoms are usually mild, severe complications may arise, and some even lead to death. Such concerns, coupled with the lack of approved vaccines and antivirals to date, create an urgency in the identification of safe therapeutics against HFMD. The disease is mainly transmitted by enteroviruses like enterovirus A71 (EV-A71). Essential for enterovirus replication is the host protein, PI4KB. In this study, we investigate the antiviral efficacy of a novel PI4KB inhibitor, CUR-N399. We found that CUR-N399 displayed broad-spectrum antiviral activity against picornaviruses in cell culture models. Using a suckling mouse model of lethal EV-A71 infection, CUR-N399 was found to be well-tolerated, promote survival and reduce viral titre in mice organs. Together, these support the discovery of CUR-N399 as an antiviral against EV-A71 and potentially other closely related viruses. • There are currently no approved treatments and vaccines for Enterovirus A71. • CUR-N399 displays broad-spectrum antiviral effects in vitro, against viruses in the Picornaviridae family. • CUR-N399 increases survival in a lethal suckling mouse model of EV-A71 infection. • A corresponding reduction in viral titre in the limb and brain is observed upon treatment with CUR-N399. • Antiviral effects of CUR-N399 can be attributed to its inhibition of PI4KB, a host protein essential for viral replication. [ABSTRACT FROM AUTHOR]