Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1

verfasst von

Paula M. Perin, Sibylle Haid, Richard J.P. Brown, Juliane Doerrbecker, Kai Schulze, Carsten Zeilinger, Markus von Schaewen, Brigitte Heller, Koen Vercauteren, Eva Luxenburger, Yasmine M. Baktash, Florian W.R. Vondran, Sietkse Speerstra, Abdullah Awadh, Furkat Mukhtarov, Luis M. Schang, Andreas Kirschning, Rolf Müller, Carlos A. Guzman, Lars Kaderali, Glenn Randall, Philip Meuleman, Alexander Ploss, Thomas Pietschmann

Abstract

To explore mechanisms of hepatitis C viral (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. Conclusion: These observations reveal novel details about HCV membrane fusion; moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as a cost-effective component of HCV combination therapies.

Organisationseinheit(en)

Zentrum für Biomolekulare Wirkstoffe (BMWZ)
Institut für Organische Chemie

Externe Organisation(en)

Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Princeton University
Universiteit Gent
Universität des Saarlandes
University of Chicago
Medizinische Hochschule Hannover (MHH)
University of Alberta
Technische Universität Dresden
TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
Deutsches Zentrum für Infektionsforschung (DZIF)

Typ

Artikel

Journal

Hepatology

Band

63

Seiten

49-62

Anzahl der Seiten

14

ISSN

0270-9139

Publikationsdatum

06.08.2015

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Hepatologie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1002/hep.28111 (Zugang: Unbekannt)