Viral polymerase binding and broad-spectrum antiviral activity of molnupiravir against human seasonal coronaviruses

Highlights

• Successfully modelled the RdRp structure of three seasonal coronaviruses.

• Molnupiravir has similar binding affinity to the RdRp of SARS-CoV-2 and seasonal coronaviruses shown by molecular docking.

• Molnupiravir effectively inhibited viral replication and production of infectious viruses of seasonal coronaviruses.

• The combination of molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity.

Abstract

Endemic seasonal coronaviruses cause morbidity and mortality in a subset of patients, but no specific treatment is available. Molnupiravir is a promising pipeline antiviral drug for treating SARS-CoV-2 infection potentially by targeting RNA-dependent RNA polymerase (RdRp). This study aims to evaluate the potential of repurposing molnupiravir for treating seasonal human coronavirus (HCoV) infections. Molecular docking revealed that the active form of molnupiravir, β-D-N⁴-hydroxycytidine (NHC), has similar binding affinity to RdRp of SARS-CoV-2 and seasonal HCoV-NL63, HCoV-OC43 and HCoV-229E. In cell culture models, treatment of molnupiravir effectively inhibited viral replication and production of infectious viruses of the three seasonal coronaviruses. A time-of-drug-addition experiment indicates the specificity of molnupiravir in inhibiting viral components. Furthermore, combining molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity. Our findings highlight the great potential of repurposing molnupiravir for treating seasonal coronavirus infected patients.