Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Autor: Ahmed Atef Ahmed Abouzeid Mesalam, Véronique Descamps, Czeslaw Wychowski, Sevser Sahpaz, Sandrine Belouzard, Véronique Pène, Marie-Emmanuelle Sahuc, Priscille Brodin, Noémie Calland, Gilles Duverlie, Karin Séron, Yves Rouillé, Philip Meuleman, Arielle R. Rosenberg, Olivier Lambert, Gaspard Deloison, Pierre Bonnafous, Jean Dubuisson
Přispěvatelé: Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Virologie de l'hépatite C (EA 4474), Université Paris Descartes - Paris 5 (UPD5), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, This work was supported by the French Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) and by the Agence Nationale de Recherche (ANR-10-EQPX-04-01) and the Feder (12001407 [D-AL] Equipex Imaginex BioMed). A.A.M. is the recipient of a Ph.D. fellowship provided by the Egyptian Government. P.M. is supported by a concerted research action grant (01G01712) from Ghent University., We thank Takaji Wakita for providing essential reagents. We thank François Helle, Stéphane Lobbens, and Cécile Lecoeur for helpful discussions and Marion Giard for technical assistance. We are grateful to Sophana Ung for his assistance with the illustrations., Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), Agents infectieux, résistance et chimiothérapie (UPJV EA4294 - AGIR )
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Journal of Virology
Journal of Virology, American Society for Microbiology, 2015, 89 (19), pp.10053-10063. ⟨10.1128/JVI.01473-15⟩
Journal of Virology, 2015, 89 (19), pp.10053-10063. ⟨10.1128/JVI.01473-15⟩
ISSN: 0022-538X
1098-5514
DOI: 10.1128/JVI.01473-15⟩
Popis: Despite the validation of direct-acting antivirals for hepatitis C treatment, the discovery of new compounds with different modes of action may still be of importance for the treatment of special patient populations. We recently identified a natural molecule, epigallocatechin-3-gallate (EGCG), as an inhibitor of hepatitis C virus (HCV) targeting the viral particle. The aim of this work was to discover new natural compounds with higher anti-HCV activity than that of EGCG and determine their mode of action. Eight natural molecules with structure similarity to EGCG were selected. HCV JFH1 in cell culture and HCV pseudoparticle systems were used to determine the antiviral activity and mechanism of action of the compounds. We identified delphinidin, a polyphenol belonging to the anthocyanidin family, as a new inhibitor of HCV entry. Delphinidin inhibits HCV entry in a pangenotypic manner by acting directly on the viral particle and impairing its attachment to the cell surface. Importantly, it is also active against HCV in primary human hepatocytes, with no apparent cytotoxicity and in combination with interferon and boceprevir in cell culture. Different approaches showed that neither aggregation nor destruction of the particle occurred. Cryo-transmission electron microscopy observations of HCV pseudoparticles treated with delphinidin or EGCG showed a bulge on particles that was not observed under control conditions. In conclusion, EGCG and delphinidin inhibit HCV entry by a new mechanism, i.e., alteration of the viral particle structure that impairs its attachment to the cell surface. IMPORTANCE In this article, we identify a new inhibitor of hepatitis C virus (HCV) infection, delphinidin, that prevents HCV entry. This natural compound, a plant pigment responsible for the blue-purple color of flowers and berries, belongs to the flavonoid family, like the catechin EGCG, the major component present in green tea extract, which is also an inhibitor of HCV entry. We studied the mode of action of these two compounds against HCV and demonstrated that they both act directly on the virus, inducing a bulging of the viral envelope. This deformation might be responsible for the observed inhibition of virus attachment to the cell surface. The discovery of such HCV inhibitors with an unusual mode of action is important to better characterize the mechanism of HCV entry into hepatocytes and to help develop a new class of HCV entry inhibitors.
Databáze: OpenAIRE
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