title: Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Perin
authors.affiliation: 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.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Haid
authors.affiliation: 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.
authors.forename: Richard J P
authors.initials: RJ
authors.lastname: Brown
authors.affiliation: 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.
authors.forename: Juliane
authors.initials: J
authors.lastname: Doerrbecker
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre of Infection Research, Braunschweig, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schulze
authors.affiliation: Institute of Organic Chemistry and Center of Biomolecular Drug Research, Leibniz Universität, Hannover, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Zeilinger
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Markus
authors.initials: M
authors.lastname: von Schaewen
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Heller
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Vercauteren
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Luxenburger
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, IL.
authors.forename: Yasmine M
authors.initials: YM
authors.lastname: Baktash
authors.affiliation: ReMediES, Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany.|German Centre for Infection Research, Hannover-Braunschweig, Germany.
authors.forename: Florian W R
authors.initials: FW
authors.lastname: Vondran
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.|Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sietkse
authors.initials: S
authors.lastname: Speerstra
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.|Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Awadh
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.|Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Furkat
authors.initials: F
authors.lastname: Mukhtarov
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.|Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.|Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Schang
authors.affiliation: Institute of Organic Chemistry and Center of Biomolecular Drug Research, Leibniz Universität, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschning
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre of Infection Research, Braunschweig, Germany.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzman
authors.affiliation: Technical University Dresden, Dresden, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, IL.
authors.forename: Glenn
authors.initials: G
authors.lastname: Randall
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.affiliation: 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.|German Centre for Infection Research, Hannover-Braunschweig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D002478:Cells, Cultured; D005444:Flunarizine / Q000494:pharmacology*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D014760:Viral Fusion Proteins / Q000187:drug effects* / Q000235:genetics; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D014760:Viral Fusion Proteins; D005444:Flunarizine