Discovery And Characterization of Small Molecule Inhibitors of Zika Virus Replication

Zika virus (ZIKV) is a flavivirus, and ZIKV infections in the past 15 years have been linked to Guillain-Barre syndrome and severe complications during pregnancy associated with congenital Zika syndrome. There are no approved therapies or vaccines for ZIKV. In recent years, advances in structure-based drug design methodologies have accelerated drug development pipelines for identifying promising inhibitory compounds against viral diseases. Among ZIKV proteins, NS2B-NS3 protease is an attractive target for antiviral drug development due to its vital role in the proteolytic processing of the single polyprotein. To find potential inhibitors against ZIKV, we used molecular docking at the NS2B-NS3 protease active site as a virtual screening approach with small molecules diverse scaffold-based library with rigorous druglikeness filters. The top-hit compounds with stable molecular dynamics trajectories were then subjected to in-vitro efficacy testing against ZIKV. In docking and molecular dynamics simulation studies, compound F1289-0194 showed stable binding to the NS2B-NS3 protease active site. Furthermore, viral load assays, immunofluorescence, and plaque reduction assays demonstrated that compound F1289-0194 significantly reduced ZIKV load and replication in Vero cells while maintaining cellular integrity. Thus, the compound F1289-0194 merits further investigation as a novel inhibitor against ZIKV replication.