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

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

doi:10.1002/hep.28111

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

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 KaderaliGlenn Randall, Philip Meuleman, Alexander Ploss, Thomas Pietschmann

Clinical Virology

Research output: Contribution to journal › A1: Web of Science-article › peer-review

Abstract

UNLABELLED: 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.

Original language	English
Journal	ISRN Hepatology
Volume	63
Issue number	1
Pages (from-to)	49-62
Number of pages	14
ISSN	2314-4041
DOIs	https://doi.org/10.1002/hep.28111
Publication status	Published - 2016

Keywords

Cells, Cultured
Flunarizine/pharmacology
Genotype
Hepacivirus/drug effects
Humans
Viral Fusion Proteins/drug effects
Virus Internalization/drug effects

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10.1002/hep.28111

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Perin, P. M., Haid, S., Brown, R. J. P., Doerrbecker, J., Schulze, K., Zeilinger, C., von Schaewen, M., Heller, B., Vercauteren, K., Luxenburger, E., Baktash, Y. M., Vondran, F. W. R., Speerstra, S., Awadh, A., Mukhtarov, F., Schang, L. M., Kirschning, A., Müller, R., Guzman, C. A., ... Pietschmann, T. (2016). Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. ISRN Hepatology, 63(1), 49-62. https://doi.org/10.1002/hep.28111

@article{25b965021d1e4218806920ada7b5c669,

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

abstract = "UNLABELLED: 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.",

keywords = "Cells, Cultured, Flunarizine/pharmacology, Genotype, Hepacivirus/drug effects, Humans, Viral Fusion Proteins/drug effects, Virus Internalization/drug effects",

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

note = "{\textcopyright} 2015 by the American Association for the Study of Liver Diseases.",

year = "2016",

doi = "10.1002/hep.28111",

language = "English",

volume = "63",

pages = "49--62",

journal = "ISRN Hepatology",

issn = "2314-4041",

publisher = "John Wiley & Sons",

number = "1",

}

Perin, 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 2016, 'Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1', ISRN Hepatology, vol. 63, no. 1, pp. 49-62. https://doi.org/10.1002/hep.28111

TY - JOUR

T1 - Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1

AU - Perin, Paula M

AU - Haid, Sibylle

AU - Brown, Richard J P

AU - Doerrbecker, Juliane

AU - Schulze, Kai

AU - Zeilinger, Carsten

AU - von Schaewen, Markus

AU - Heller, Brigitte

AU - Vercauteren, Koen

AU - Luxenburger, Eva

AU - Baktash, Yasmine M

AU - Vondran, Florian W R

AU - Speerstra, Sietkse

AU - Awadh, Abdullah

AU - Mukhtarov, Furkat

AU - Schang, Luis M

AU - Kirschning, Andreas

AU - Müller, Rolf

AU - Guzman, Carlos A

AU - Kaderali, Lars

AU - Randall, Glenn

AU - Meuleman, Philip

AU - Ploss, Alexander

AU - Pietschmann, Thomas

PY - 2016

Y1 - 2016

N2 - UNLABELLED: 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.

AB - UNLABELLED: 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.

KW - Cells, Cultured

KW - Flunarizine/pharmacology

KW - Genotype

KW - Hepacivirus/drug effects

KW - Humans

KW - Viral Fusion Proteins/drug effects

KW - Virus Internalization/drug effects

U2 - 10.1002/hep.28111

DO - 10.1002/hep.28111

M3 - A1: Web of Science-article

C2 - 26248546

SN - 2314-4041

VL - 63

SP - 49

EP - 62

JO - ISRN Hepatology

JF - ISRN Hepatology

IS - 1

ER -

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

Abstract

Keywords

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