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

FEBS Lett. 2014 May 2;588(9):1720-5. doi: 10.1016/j.febslet.2014.03.021. Epub 2014 Mar 18.

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 IC50vs. 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.

Keywords: Antiviral discovery; In silico-docking; Norovirus; PPNDS; RNA-dependent-RNA-polymerase; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Mice
  • Models, Molecular
  • Norovirus / enzymology*
  • Protein Binding
  • Protein Structure, Secondary
  • Pyridoxal Phosphate / analogs & derivatives*
  • Pyridoxal Phosphate / chemistry
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • RNA-Dependent RNA Polymerase / chemistry*
  • Sulfonic Acids / chemistry*
  • Viral Proteins / antagonists & inhibitors
  • Viral Proteins / chemistry*

Substances

  • Antiviral Agents
  • Sulfonic Acids
  • Viral Proteins
  • pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate)
  • Pyridoxal Phosphate
  • RNA-Dependent RNA Polymerase

Associated data

  • PDB/4O4R