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

2.50
Hdl Handle:
http://hdl.handle.net/10033/596344
Title:
Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1.
Authors:
Perin, Paula M; Haid, Sibylle; Brown, Richard J P; Doerrbecker, Juliane; Schulze, Kai; Zeilinger, Carsten; von Schaewen, Markus; Heller, Brigitte; Vercauteren, Koen; Luxenburger, Eva; Baktash, Yasmine M; Vondran, Florian W R; Speerstra, Sietkse; Awadh, Abdullah; Mukhtarov, Furkat; Schang, Luis M; Kirschning, Andreas; Müller, Rolf; Guzman, Carlos A; Kaderali, Lars; Randall, Glenn; Meuleman, Philip; Ploss, Alexander; 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.
Affiliation:
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Citation:
Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. 2016, 63 (1):49-62 Hepatology
Journal:
Hepatology (Baltimore, Md.)
Issue Date:
Jan-2016
URI:
http://hdl.handle.net/10033/596344
DOI:
10.1002/hep.28111
PubMed ID:
26248546
Type:
Article
Language:
en
ISSN:
1527-3350
Appears in Collections:
publications of the department experimental Virology([TC]EVIR)

Full metadata record

DC FieldValue Language
dc.contributor.authorPerin, Paula Men
dc.contributor.authorHaid, Sibylleen
dc.contributor.authorBrown, Richard J Pen
dc.contributor.authorDoerrbecker, Julianeen
dc.contributor.authorSchulze, Kaien
dc.contributor.authorZeilinger, Carstenen
dc.contributor.authorvon Schaewen, Markusen
dc.contributor.authorHeller, Brigitteen
dc.contributor.authorVercauteren, Koenen
dc.contributor.authorLuxenburger, Evaen
dc.contributor.authorBaktash, Yasmine Men
dc.contributor.authorVondran, Florian W Ren
dc.contributor.authorSpeerstra, Sietkseen
dc.contributor.authorAwadh, Abdullahen
dc.contributor.authorMukhtarov, Furkaten
dc.contributor.authorSchang, Luis Men
dc.contributor.authorKirschning, Andreasen
dc.contributor.authorMüller, Rolfen
dc.contributor.authorGuzman, Carlos Aen
dc.contributor.authorKaderali, Larsen
dc.contributor.authorRandall, Glennen
dc.contributor.authorMeuleman, Philipen
dc.contributor.authorPloss, Alexanderen
dc.contributor.authorThomas, Pietschmannen
dc.date.accessioned2016-02-16T14:38:17Zen
dc.date.available2016-02-16T14:38:17Zen
dc.date.issued2016-01en
dc.identifier.citationFlunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. 2016, 63 (1):49-62 Hepatologyen
dc.identifier.issn1527-3350en
dc.identifier.pmid26248546en
dc.identifier.doi10.1002/hep.28111en
dc.identifier.urihttp://hdl.handle.net/10033/596344en
dc.description.abstractTo 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.en
dc.language.isoenen
dc.titleFlunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1.en
dc.typeArticleen
dc.contributor.departmentTWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.en
dc.identifier.journalHepatology (Baltimore, Md.)en

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