A Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes.

2.50
HDL Handle:
http://hdl.handle.net/10033/225602
Title:
A Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes.
Authors:
Haid, Sibylle; Novodomská, Alexandra; Gentzsch, Juliane; Grethe, Christina; Geuenich, Silvia; Bankwitz, Dorothea; Chhatwal, Patrick; Jannack, Beate; Hennebelle, Thierry; Bailleul, Francois; Keppler, Oliver T; Pönisch, Marion; Bartenschlager, Ralf; Hernandez, Céline; Lemasson, Matthieu; Rosenberg, Arielle; Wong-Staal, Flossie; Davioud-Charvet, Elisabeth; Pietschmann, Thomas
Abstract:
BACKGROUND & AIMS: 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.
Affiliation:
Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
Citation:
A Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes. 2012:notGastroenterology
Journal:
Gastroenterology
Issue Date:
27-Mar-2012
URI:
http://hdl.handle.net/10033/225602
DOI:
10.1053/j.gastro.2012.03.036
PubMed ID:
22465429
Type:
Article
ISSN:
1528-0012
Appears in Collections:
Publications of the Twincore unit Experimental Virology(EVIR)

Full metadata record

DC FieldValueLanguage
dc.contributor.authorHaid, Sibylleen_GB
dc.contributor.authorNovodomská, Alexandraen_GB
dc.contributor.authorGentzsch, Julianeen_GB
dc.contributor.authorGrethe, Christinaen_GB
dc.contributor.authorGeuenich, Silviaen_GB
dc.contributor.authorBankwitz, Dorotheaen_GB
dc.contributor.authorChhatwal, Patricken_GB
dc.contributor.authorJannack, Beateen_GB
dc.contributor.authorHennebelle, Thierryen_GB
dc.contributor.authorBailleul, Francoisen_GB
dc.contributor.authorKeppler, Oliver Ten_GB
dc.contributor.authorPönisch, Marionen_GB
dc.contributor.authorBartenschlager, Ralfen_GB
dc.contributor.authorHernandez, Célineen_GB
dc.contributor.authorLemasson, Matthieuen_GB
dc.contributor.authorRosenberg, Arielleen_GB
dc.contributor.authorWong-Staal, Flossieen_GB
dc.contributor.authorDavioud-Charvet, Elisabethen_GB
dc.contributor.authorPietschmann, Thomasen_GB
dc.date.accessioned2012-05-23T14:24:09Z-
dc.date.available2012-05-23T14:24:09Z-
dc.date.issued2012-03-27-
dc.identifier.citationA Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes. 2012:notGastroenterologyen_GB
dc.identifier.issn1528-0012-
dc.identifier.pmid22465429-
dc.identifier.doi10.1053/j.gastro.2012.03.036-
dc.identifier.urihttp://hdl.handle.net/10033/225602-
dc.description.abstractBACKGROUND & AIMS: 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.en_GB
dc.languageENG-
dc.rightsArchived with thanks to Gastroenterologyen_GB
dc.titleA Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes.-
dc.typeArticleen
dc.contributor.departmentDivision of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.en_GB
dc.identifier.journalGastroenterologyen_GB

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