title: New pseudodimeric aurones as palm pocket inhibitors of Hepatitis C virus RNA-dependent RNA polymerase.
abstract: The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 μM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives.
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France.
authors.forename: Amel
authors.initials: A
authors.lastname: Meguellati
authors.affiliation: INSERM U955, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Ahmed-Belkacem
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: INSERM U955, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Brillet
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France.
authors.forename: Nawel
authors.initials: N
authors.lastname: Berqouch
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Chavoutier
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Fortuné
authors.affiliation: INSERM U955, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: Univ. Grenoble Alpes, Département de Pharmacochimie Moléculaire DPM, UMR 5063, 38041 Grenoble, France; CNRS, DPM, UMR 5063, 38041 Grenoble, France. Electronic address: Marine.Peuchmaur@ujf-grenoble.fr.
authors.forename: Marine
authors.initials: M
authors.lastname: Peuchmaur
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C486837:aurone; D012324:RNA-Dependent RNA Polymerase
keywords: Aurones; Hepatitis C virus; RNA-dependent RNA polymerase