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

TitleFlunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1.
Publication TypeJournal Article
Year of Publication2016
AuthorsPerin, PM, Haid, S, Brown, RJP, Doerrbecker, J, Schulze, K, Zeilinger, C, von Schaewen, M, Heller, B, Vercauteren, K, Luxenburger, E, Baktash, YM, Vondran, FWR, Speerstra, S, Awadh, A, Mukhtarov, F, Schang, LM, Kirschning, A, Müller, R, Guzman, CA, Kaderali, L, Randall, G, Meuleman, P, Ploss, A, Pietschmann, T
JournalHepatology
Volume63
Issue1
Pagination49-62
Date Published2016 Jan
ISSN1527-3350
KeywordsCells, Cultured, Flunarizine, Genotype, Hepacivirus, Humans, Viral Fusion Proteins, Virus Internalization
Abstract

<p><b>UNLABELLED: </b>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.</p><p><b>CONCLUSION: </b>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.</p>

DOI10.1002/hep.28111
Alternate JournalHepatology
PubMed ID26248546
PubMed Central IDPMC4688136
Grant ListR01 AI107301 / AI / NIAID NIH HHS / United States
R21 AI117213 / AI / NIAID NIH HHS / United States
5R01AI107301 / AI / NIAID NIH HHS / United States
MOP130333 / / Canadian Institutes of Health Research / Canada