Non-nucleoside Inhibitors of Zika Virus RNA-Dependent RNA Polymerase
Copyright policy )Non-nucleoside Inhibitors of Zika Virus RNA-Dependent RNA Polymerase
Zika virus belongs to the Flavivirus 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.
- National University of Singapore Singapore
- Nanyang Technological University Singapore
- Duke NUS Graduate Medical School Singapore
- Nationl University of Singapore Singapore
- Griffith University Australia
Models, Molecular, Protein Conformation, alpha-Helical, Biomedical and clinical sciences, Gene Expression, Antiviral Agents, Polymerase Inhibitors, Zika virus, Nonstructural Protein 5, Cricetulus, veterinary and food sciences, Allosteric Regulation, nonstructural protein 5, Cell Line, Tumor, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Agricultural, Binding Sites, RNA polymerases, :Biological sciences [Science], RNA-Dependent RNA Polymerase, Recombinant Proteins, Biological sciences, Kinetics, Drug Design, Hepatocytes, polymerase inhibitors, Protein Conformation, beta-Strand, Allosteric Site, Protein Binding
Models, Molecular, Protein Conformation, alpha-Helical, Biomedical and clinical sciences, Gene Expression, Antiviral Agents, Polymerase Inhibitors, Zika virus, Nonstructural Protein 5, Cricetulus, veterinary and food sciences, Allosteric Regulation, nonstructural protein 5, Cell Line, Tumor, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Agricultural, Binding Sites, RNA polymerases, :Biological sciences [Science], RNA-Dependent RNA Polymerase, Recombinant Proteins, Biological sciences, Kinetics, Drug Design, Hepatocytes, polymerase inhibitors, Protein Conformation, beta-Strand, Allosteric Site, Protein Binding
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