title: Discovery of novel dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design.
abstract: With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase. We considered linking two of them, which bind to proximal sites of the AdoMet binding pocket, in order to improve their potency. X-ray crystallographic structures and computational docking were used to guide the fragment linking, ultimately leading to novel series of non-nucleoside inhibitors of flavivirus MTase, respectively N-phenyl-[(phenylcarbamoyl)amino]benzene-1-sulfonamide and phenyl [(phenylcarbamoyl)amino]benzene-1-sulfonate derivatives, that show a 10-100-fold stronger inhibition of 2'-O-MTase activity compared to the initial fragments.
authors.affiliation: Aix-Marseille Université, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Benmansour
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
authors.forename: Iuni
authors.initials: I
authors.lastname: Trist
authors.affiliation: Aix-Marseille Université, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Coutard
authors.affiliation: Aix-Marseille Université, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Decroly
authors.affiliation: UMR "Emergence des Pathologies Virales" (EPV: Aix-Marseille university - IRD 190 - Inserm 1207 - EHESP), & Fondation IHU Méditerranée Infection, APHM Public Hospitals of Marseille, Marseille, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Querat
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Aix-Marseille Université, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille cedex 09, France; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: karine.barral@inserm.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Barral
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003716:Dengue Virus / Q000201:enzymology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D013431:Sulfates / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; C582223:NS5 protein, dengue virus; D013431:Sulfates; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D008780:Methyltransferases
keywords: Antiviral activity; Dengue virus; Fragment-linking strategy; N-Phenyl-[(phenylcarbamoyl)amino]benzene-1-sulfonamide derivatives; NS5 methyltransferase inhibitors; Phenyl [(phenylcarbamoyl)amino]benzene-1-sulfonate derivatives