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.
Romina Croci  1 ,  Delia Tarantino  1 ,  Mario Milani  2 ,  Margherita Pezzullo  2 ,  Jacques Rohayem  3 ,  Martino Bolognesi  1 ,  Eloise Mastrangelo  4
Affiliations
  • 1. Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy.
  • 2. Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy; CNR-IBF, Istituto di Biofisica, Via Celoria 26, I-20133 Milano, Italy.
  • 3. Institute of Virology, Dresden University of Technology, Fiedlerstrasse 42, 01307 Dresden, Germany; Riboxx GmbH, Pharmapark Radebeul, Meissner Strasse 191, 01445 Radebeul, Germany.
  • 4. Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy; CNR-IBF, Istituto di Biofisica, Via Celoria 26, I-20133 Milano, Italy. Electronic address: [email protected].
PMID: 24657439 DOI: 10.1016/j.febslet.2014.03.021
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.
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