title: Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle.
abstract: We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.
authors.affiliation: Molecular Biology Interdepartmental Ph.D. Program, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, California, CA, United States. RnKhch@ucla.edu
authors.forename: Ronik
authors.initials: R
authors.lastname: Khachatoorian
authors.forename: Vaithilingaraja
authors.initials: V
authors.lastname: Arumugaswami
authors.forename: Santanu
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: George K
authors.initials: GK
authors.lastname: Yeh
authors.forename: Eden M
authors.initials: EM
authors.lastname: Maloney
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.forename: Asim
authors.initials: A
authors.lastname: Dasgupta
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology; D002460:Cell Line; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D014176:Protein Biosynthesis / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000502:physiology; D014764:Viral Proteins / Q000096:biosynthesis; D019065:Virus Assembly / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002392:Catechin; D044950:Flavanones; D005419:Flavonoids; D018840:HSP70 Heat-Shock Proteins; D011794:Quercetin; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C005273:naringenin