title: Discovery of naturally occurring aurones that are potent allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
abstract: We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 aurones was rationally explored in an enzyme assay. Molecular docking studies were used to determine how aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivatives were found to have potent inhibitory effects on HCV RdRp, with IC(50) below 5 μM and excellent selectivity index (inhibition activity versus cellular cytotoxicity). The most active aurone analogue was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6-dihydroxybenzofuran-3(2H)-one (compound 51), with an IC(50) of 2.2 μM. Their potent RdRp inhibitory activity and their low toxicity make these molecules attractive candidates as direct-acting anti-HCV agents.
authors.affiliation: Département de Pharmacochimie Moléculaire, Université de Grenoble, CNRS, UMR 5063, Grenoble, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Haudecoeur
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Ahmed-Belkacem
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.forename: Antoine
authors.initials: A
authors.lastname: Fortuné
authors.forename: Rozenn
authors.initials: R
authors.lastname: Brillet
authors.forename: Catherine
authors.initials: C
authors.lastname: Belle
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicolle
authors.forename: Coralie
authors.initials: C
authors.lastname: Pallier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; C486837:aurone; D012324:RNA-Dependent RNA Polymerase