title: PPNDS inhibits murine Norovirus RNA-dependent RNA-polymerase mimicking two RNA stacking bases.
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.
authors.affiliation: Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Croci
authors.affiliation: Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Tarantino
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Milani
authors.affiliation: 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.
authors.forename: Margherita
authors.initials: M
authors.lastname: Pezzullo
authors.affiliation: Institute of Virology, Dresden University of Technology, Fiedlerstrasse 42, 01307 Dresden, Germany; Riboxx GmbH, Pharmapark Radebeul, Meissner Strasse 191, 01445 Radebeul, Germany.
authors.forename: Jacques
authors.initials: J
authors.lastname: Rohayem
authors.affiliation: Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.affiliation: 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: eloise.mastrangelo@unimi.it.
authors.forename: Eloise
authors.initials: E
authors.lastname: Mastrangelo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D029322:Norovirus / Q000201:enzymology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D013451:Sulfonic Acids; D014764:Viral Proteins; C405633:pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate); D011732:Pyridoxal Phosphate; D012324:RNA-Dependent RNA Polymerase
keywords: Antiviral discovery; In silico-docking; Norovirus; PPNDS; RNA-dependent-RNA-polymerase; X-ray crystallography