title: The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection.
abstract: The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Delang
authors.affiliation: CNRS, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.|Aix-Marseille Université, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Tas
authors.affiliation: Aix-Marseille Université, IRD French Institute of Research for Development, UMR_D 190 "Emergence des Pathologies Virales", 27 boulevard Jean-Moulin, 13005 Marseille, France.
authors.forename: G
authors.initials: G
authors.lastname: Quérat
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: I C
authors.initials: IC
authors.lastname: Albulescu
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: De Burghgraeve
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: N A Segura
authors.initials: NA
authors.lastname: Guerrero
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gigante
authors.affiliation: Aix-Marseille Université, IRD French Institute of Research for Development, UMR_D 190 "Emergence des Pathologies Virales", 27 boulevard Jean-Moulin, 13005 Marseille, France.
authors.forename: G
authors.initials: G
authors.lastname: Piorkowski
authors.affiliation: CNRS, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.|Aix-Marseille Université, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.
authors.forename: E
authors.initials: E
authors.lastname: Decroly
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Jochmans
authors.affiliation: CNRS, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.|Aix-Marseille Université, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.
authors.forename: B
authors.initials: B
authors.lastname: Canard
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Snijder
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: van Hemert
authors.affiliation: CNRS, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.|Aix-Marseille Université, AFMB UMR 7257, Avenue de Luminy 163, 13288 Marseille, France.
authors.forename: B
authors.initials: B
authors.lastname: Coutard
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Neyts
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002646:Chikungunya virus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral / Q000187:drug effects; D004683:Encephalomyelitis, Equine / Q000821:virology; D006736:Horses; D015394:Molecular Structure; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D011744:Pyrimidinones; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins