Effective repurposed antivirals against an emerging virus

The ongoing global monkeypox virus (MPXV) outbreak urgently needs effective medications, which be accelerated through drug repurposing. However, it is challenging to poinpoint protein targets. Here we introduce a novel method rooted in molecular evolutionary theory for quick drug target identification for MPXV. It identifies drug targets as positively selected genes of viral proteins which bind host proteins. From the identified targets, we select a top gene product OPG021 for virtural drug screening. One top-ranked drug nilotinib is experimentally shown to have a significant 69% of antiviral efficacy of the FDA-approved antiviral tecovirimat (TPOXX or ST-246). Higher binding affinity but not antiviral efficacy of repursposed drugs than FDA-approved drugs suggests the complexity of drug repurposing and underscores the importance of experimental validation. This innovative drug target identification strategy will contribute to combating the ongoing MPXV outbreak and other viral acute and chronic viral diseases.