Non-nucleoside Inhibitors of Zika Virus RNA-Dependent RNA Polymerase
Aïcha Gharbi-Ayachi, Sridhar Santhanakrishnan, Yee Hwa Wong, Kitti Wing Ki Chan, Siok Thing Tan, Roderick W. Bates, Subhash G. Vasudevan, Abbas El Sahili, Julien Lescar
Abstract
genus, which comprises several important human pathogens. There is currently neither an approved vaccine nor antiviral drugs available to prevent infection by ZIKV. The nonstructural protein 5 (NS5) polymerase, which is responsible for replicating the viral RNA genome, represents one of the most promising targets for antiviral drug development. Starting from compounds recently developed against dengue virus NS5, we designed and synthesized inhibitors targeting Zika virus NS5. We show that these novel compounds inhibit viral replication by targeting the polymerase activity. High-resolution X-ray crystallographic structures of protein-inhibitor complexes demonstrated specific binding to an allosteric site within the polymerase, called the N pocket. This work paves the way for the future structure-based design of potent compounds specifically targeting ZIKV RNA polymerase activity.