title: A plant-derived flavonoid inhibits entry of all HCV genotypes into human hepatocytes.
abstract: OBJECTIVE
  Interferon-based therapies for hepatitis C virus (HCV) infection are limited by side effects and incomplete response rates, particularly among transplant recipients. We screened a library of plant-derived small molecules to identify HCV inhibitors with novel mechanisms.
  
  
  METHODS
  We isolated phenolic compounds from Marrubium peregrinum L (Lamiaceae). Replication of HCV RNA, virus production, and cell entry were monitored using replicons and infectious HCV. Inhibition of HCV was measured in hepatoma cells and primary human hepatocytes using luciferase reporter gene assays, core enzyme-linked immunosorbent assays, or infectivity titration. We tested the bioavailability of the compound in mice.
  
  
  RESULTS
  We identified a flavonoid, ladanein (BJ486K), with unreported antiviral activity and established its oral bioavailability in mice. Natural and synthetic BJ486K inhibited a post-attachment entry step, but not RNA replication or assembly; its inhibitory concentration 50% was 2.5 μm. BJ486K was effective against all major HCV genotypes, including a variant that is resistant to an entry inhibitor; it prevented infection of primary human hepatocytes. Combined administration of BJ486K and cyclosporine A had a synergistic effect in inhibition of HCV infection.
  
  
  CONCLUSIONS
  BJ486K has oral bioavailability and interferes with entry of HCV into cultured human hepatocytes. It synergizes with cyclosporine A to inhibit HCV infection. Its inhibitory effects are independent of HCV genotype, including a variant that is resistant to an entry inhibitor against scavenger receptor class B type I. Flavonoid derivatives therefore might be developed as components of combination therapies because they are potent, broadly active inhibitors of HCV entry that could prevent graft reinfection after liver transplantation.
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Haid
authors.forename: Alexandra
authors.initials: A
authors.lastname: Novodomská
authors.forename: Juliane
authors.initials: J
authors.lastname: Gentzsch
authors.forename: Christina
authors.initials: C
authors.lastname: Grethe
authors.forename: Silvia
authors.initials: S
authors.lastname: Geuenich
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bankwitz
authors.forename: Patrick
authors.initials: P
authors.lastname: Chhatwal
authors.forename: Beate
authors.initials: B
authors.lastname: Jannack
authors.forename: Thierry
authors.initials: T
authors.lastname: Hennebelle
authors.forename: Francois
authors.initials: F
authors.lastname: Bailleul
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
authors.forename: Marion
authors.initials: M
authors.lastname: Poenisch
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Céline
authors.initials: C
authors.lastname: Hernandez
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lemasson
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Rosenberg
authors.forename: Flossie
authors.initials: F
authors.lastname: Wong-Staal
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D047309:Flavones / Q000494:pharmacology*; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D027522:Marrubium; D008517:Phytotherapy; D010936:Plant Extracts / Q000627:therapeutic use; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D047309:Flavones; D010936:Plant Extracts; C549432:ladanein