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Hepatology. 2016 Jan;63(1):49-62. doi: 10.1002/hep.28111. Epub 2015 Oct 9.

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

Author information

1
Institute 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.
2
Department of Vaccinology and Applied Microbiology, Helmholtz Centre of Infection Research, Braunschweig, Germany.
3
Institute of Organic Chemistry and Center of Biomolecular Drug Research, Leibniz Universität, Hannover, Germany.
4
Department of Molecular Biology, Princeton University, Princeton, NJ.
5
Center for Vaccinology, Ghent University, Ghent, Belgium.
6
Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
7
Department of Microbiology, The University of Chicago, Chicago, IL.
8
ReMediES, Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
9
German Centre for Infection Research, Hannover-Braunschweig, Germany.
10
Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
11
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.
12
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
13
Technical University Dresden, Dresden, Germany.

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.

PMID:
26248546
PMCID:
PMC4688136
DOI:
10.1002/hep.28111
[Indexed for MEDLINE]
Free PMC Article

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