title: Ex vivo and in vivo inhibition of human rhinovirus replication by a new pseudosubstrate of viral 2A protease.
abstract: Human rhinoviruses (HRVs) remain a significant public health problem as they are the major cause of both upper and lower respiratory tract infections. Unfortunately, to date no vaccine or antiviral against these pathogens is available. Here, using a high-throughput yeast two-hybrid screening, we identified a 6-amino-acid hit peptide, LVLQTM, which acted as a pseudosubstrate of the viral 2A cysteine protease (2A(pro)) and inhibited its activity. This peptide was chemically modified with a reactive electrophilic fluoromethylketone group to form a covalent linkage with the nucleophilic active-site thiol of the enzyme. Ex vivo and in vivo experiments showed that thus converted, LVLQTM was a strong inhibitor of HRV replication in both A549 cells and mice. To our knowledge, this is the first report validating a compound against HRV infection in a mouse model.
authors.affiliation: VirPath, EMR 4610, Virologie et Pathologie Humaine, Université Lyon 1, Université de Lyon, Faculté de Médecine Lyon-Est, Secteur Laennec, Lyon, France.
authors.forename: Nisrine
authors.initials: N
authors.lastname: Falah
authors.forename: Sébastien
authors.initials: S
authors.lastname: Violot
authors.forename: Didier
authors.initials: D
authors.lastname: Décimo
authors.forename: Fatma
authors.initials: F
authors.lastname: Berri
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Foucault-Grunenwald
authors.forename: Théophile
authors.initials: T
authors.lastname: Ohlmann
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schuffenecker
authors.forename: Florence
authors.initials: F
authors.lastname: Morfin
authors.forename: Bruno
authors.initials: B
authors.lastname: Lina
authors.forename: Béatrice
authors.initials: B
authors.lastname: Riteau
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Cortay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010850:Picornaviridae Infections / Q000821:virology*; D011485:Protein Binding; D012229:Rhinovirus / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D013379:Substrate Specificity; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D010455:Peptides; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; C057400:picornain 2A, Picornavirus
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