Details
| Original language | English |
|---|---|
| Pages (from-to) | 49-62 |
| Number of pages | 14 |
| Journal | Hepatology |
| Volume | 63 |
| Issue number | 1 |
| Publication status | Published - 6 Aug 2015 |
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.
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In: Hepatology, Vol. 63, No. 1, 06.08.2015, p. 49-62.
Research output: Contribution to journal › Article › Research › peer review
}
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 - 2015/8/6
Y1 - 2015/8/6
N2 - 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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=84952639370&partnerID=8YFLogxK
U2 - 10.1002/hep.28111
DO - 10.1002/hep.28111
M3 - Article
C2 - 26248546
AN - SCOPUS:84952639370
VL - 63
SP - 49
EP - 62
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 1
ER -