Phenotypic-Based Discovery of Zika Virus Protease Inhibitors with Potent Cellular and In Vivo Activity

About this poster

Zika virus (ZIKV) continues to pose public health concerns due to its association with congenital and neurological complications, and currently, there are no approved antiviral therapies. This poster outlines an integrated drug discovery campaign at IRBM: it begins with a stable ZIKV sub-genomic replicon assay optimized for high-throughput phenotypic screening and traces target identification through resistance mapping and reverse genetics, pinpointing the NS2B–NS3 protease as the molecular target. Using X-ray crystallography, kinetic analysis, and medicinal chemistry, the team characterized a novel allosteric binding site and optimized an initial hit into IRBM-Z-2, a nanomolar inhibitor with broad-spectrum activity, a favorable off-target profile, and oral efficacy in mouse infection models. Download the poster to explore the complete screening process, structural data, and detailed in vivo efficacy results.