Antiviral synergy between Zika virus protease and polymerase inhibitors

Abstract

Zika virus (ZIKV) infection may be associated with congenital malformations in infected fetuses and severe complications in infected adults. There are limited treatment options that are readily available. We previously reported the in vitro and in vivo antiviral activity of novobiocin against the closely related Zika virus through inhibition of the Zika virus NS2B-NS3 protease. In this study, we investigated the antiviral activity of combinational novobiocin (protease inhibitor) and ribavirin (polymerase inhibitor) against ZIKV. The in vitro anti-ZIKV activities of novobiocin and ribavirin were individually assessed in multiple cell lines using cytopathic effect inhibition, viral load reduction, and plaque reduction assays, followed by checkerboard assay for combinational effect. While both drugs significantly inhibited ZIKV in vitro when given alone, their combinational effect was synergistic (Loewe additivity index <1). Molecular docking predicted that novobiocin and ribavirin bound to the ZIKV protease and polymerase, respectively, with high stability. Our study showed that combinational treatment targeting multiple enzymes of ZIKV achieved better in vitro anti-ZIKV activity. Further studies should be conducted to explore other clinically available combinations of ZIKV enzyme inhibitors to facilitate the development of effective treatments against this emerging infection.