Norovirus (NV) is a major cause of gastroenteritis worldwide. Antivirals against such important pathogens are on demand. Among the viral proteins that orchestrate viral replication, RNA-dependent-RNA-polymerase (RdRp) is a promising drug development target. From an in silico-docking search focused on the RdRp active site, we selected the compound PPNDS, which showed low micromolar IC50 vs. murine NV-RdRp in vitro. We report the crystal structure of the murine NV-RdRp/PPNDS complex showing that two molecules of the inhibitor bind in antiparallel stacking interaction, properly oriented to block exit of the newly synthesized RNA. Such inhibitor-binding mode mimics two stacked nucleotide-bases of the RdRp/ssRNA complex. © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

PPNDS inhibits murine Norovirus RNA-dependent RNA-polymerase mimicking two RNA stacking bases

PEZZULLO, MARGHERITA;
2014-01-01

Abstract

Norovirus (NV) is a major cause of gastroenteritis worldwide. Antivirals against such important pathogens are on demand. Among the viral proteins that orchestrate viral replication, RNA-dependent-RNA-polymerase (RdRp) is a promising drug development target. From an in silico-docking search focused on the RdRp active site, we selected the compound PPNDS, which showed low micromolar IC50 vs. murine NV-RdRp in vitro. We report the crystal structure of the murine NV-RdRp/PPNDS complex showing that two molecules of the inhibitor bind in antiparallel stacking interaction, properly oriented to block exit of the newly synthesized RNA. Such inhibitor-binding mode mimics two stacked nucleotide-bases of the RdRp/ssRNA complex. © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
2014
Antiviral discovery; In silico-docking; Norovirus; PPNDS; RNA-dependent-RNA-polymerase; X-ray crystallography; Animals; Antiviral Agents; Catalytic Domain; Crystallography; X-Ray; Mice; Models; Molecular; Protein Binding; Protein Structure; Secondary; Pyridoxal Phosphate; RNA Replicase; Sulfonic Acid s; Viral Proteins; Biochemistry; Biophysics; Cell Biology; Genetics; Molecular Biology; Structural Biology
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/76888
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