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dc.contributor.authorHaid, Sibylle
dc.contributor.authorNovodomská, Alexandra
dc.contributor.authorGentzsch, Juliane
dc.contributor.authorGrethe, Christina
dc.contributor.authorGeuenich, Silvia
dc.contributor.authorBankwitz, Dorothea
dc.contributor.authorChhatwal, Patrick
dc.contributor.authorJannack, Beate
dc.contributor.authorHennebelle, Thierry
dc.contributor.authorBailleul, Francois
dc.contributor.authorKeppler, Oliver T
dc.contributor.authorPönisch, Marion
dc.contributor.authorBartenschlager, Ralf
dc.contributor.authorHernandez, Céline
dc.contributor.authorLemasson, Matthieu
dc.contributor.authorRosenberg, Arielle
dc.contributor.authorWong-Staal, Flossie
dc.contributor.authorDavioud-Charvet, Elisabeth
dc.contributor.authorPietschmann, Thomas
dc.date.accessioned2012-05-23T14:24:09Zen
dc.date.available2012-05-23T14:24:09Zen
dc.date.issued2012-03-27en
dc.identifier.citationA Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes. 2012:notGastroenterologyen_GB
dc.identifier.issn1528-0012en
dc.identifier.pmid22465429en
dc.identifier.doi10.1053/j.gastro.2012.03.036en
dc.identifier.urihttp://hdl.handle.net/10033/225602en
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.
dc.languageENGen
dc.rightsArchived with thanks to Gastroenterologyen_GB
dc.titleA Plant-Derived Flavonoid Inhibits Entry of All HCV Genotypes Into Human Hepatocytes.en
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
refterms.dateFOA2018-06-13T01:09:53Z
html.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.


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