title: The enterovirus protease inhibitor rupintrivir exerts cross-genotypic anti-norovirus activity and clears cells from the norovirus replicon.
abstract: Potent and safe inhibitors of norovirus replication are needed for the treatment and prophylaxis of norovirus infections. We here report that the in vitro anti-norovirus activity of the protease inhibitor rupintrivir is extended to murine noroviruses and that rupintrivir clears human cells from their Norwalk replicon after only two passages of antiviral pressure. In addition, we demonstrate that rupintrivir inhibits the human norovirus (genogroup II [GII]) protease and further explain the inhibitory effect of the molecule by means of molecular modeling on the basis of the crystal structure of the Norwalk virus protease. The combination of rupintrivir with the RNA-dependent RNA polymerase inhibitors 2'-C-methylcytidine and favipiravir (T-705) resulted in a merely additive antiviral effect. The fact that rupintrivir is active against noroviruses belonging to genogroup I (Norwalk virus), genogroup V (murine norovirus), and the recombinant 3C-like protease of a GII norovirus suggests that the drug exerts cross-genotypic anti-norovirus activity and will thus most likely be effective against the clinically relevant human norovirus strains. The design of antiviral molecules targeting the norovirus protease could be a valuable approach for the treatment and/or prophylaxis of norovirus infections.
authors.affiliation: L. Microbiologia, D. Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Rocha-Pereira
authors.affiliation: L. Microbiologia, D. Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: M S J
authors.initials: MS
authors.lastname: Nascimento
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany German Center for Infection Research (DZIF), University of Lübeck, Lübeck, Germany.
authors.forename: Q
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany German Center for Infection Research (DZIF), University of Lübeck, Lübeck, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Hilgenfeld
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium johan.neyts@rega.kuleuven.be.
authors.forename: J
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Jochmans
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D003562:Cytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009663:Norwalk virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D010206:Papain / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012093:Replicon; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000577:Amides; D000998:Antiviral Agents; D004338:Drug Combinations; D007555:Isoxazoles; D011719:Pyrazines; D011760:Pyrrolidinones; D014764:Viral Proteins; C513402:2'-C-methylcytidine; D010649:Phenylalanine; D003562:Cytidine; D012324:RNA-Dependent RNA Polymerase; D003546:Cysteine Endopeptidases; D010206:Papain; C462182:favipiravir; D014633:Valine; C118874:rupintrivir