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

(2016) HEPATOLOGY. 63(1). p.49-62
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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.
Keywords
CALCIUM CHANNELS, E2 ENVELOPE GLYCOPROTEINS, LIFE-CYCLE, ENTRY, INFECTION, NEUROLEPTICS, INHIBITION, ACTIVATION, THERAPIES, REGIONS

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Chicago
Perin, Paula M, Sibylle Haid, Richard JP Brown, Juliane Doerrbecker, Kai Schulze, Carsten Zeilinger, Markus von Schaewen, et al. 2016. “Flunarizine Prevents Hepatitis C Virus Membrane Fusion in a Genotype-dependent Manner by Targeting the Potential Fusion Peptide Within E1.” Hepatology 63 (1): 49–62.
APA
Perin, P. M., Haid, S., Brown, R. J., Doerrbecker, J., Schulze, K., Zeilinger, C., von Schaewen, M., et al. (2016). Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. HEPATOLOGY, 63(1), 49–62.
Vancouver
1.
Perin PM, Haid S, Brown RJ, Doerrbecker J, Schulze K, Zeilinger C, et al. Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. HEPATOLOGY. 2016;63(1):49–62.
MLA
Perin, Paula M, Sibylle Haid, Richard JP Brown, et al. “Flunarizine Prevents Hepatitis C Virus Membrane Fusion in a Genotype-dependent Manner by Targeting the Potential Fusion Peptide Within E1.” HEPATOLOGY 63.1 (2016): 49–62. Print.
@article{7260265,
  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.},
  author       = {Perin, Paula M and Haid, Sibylle and Brown, Richard JP and Doerrbecker, Juliane and Schulze, Kai and Zeilinger, Carsten and von Schaewen, Markus and Heller, Brigitte and Vercauteren, Koen and Luxenburger, Eva and Baktash, Yasmine M and Vondran, Florian WR and Speerstra, Sietkse and Awadh, Abdullah and Mukhtarov, Furkat and Schang, Luis M and Kirschning, Andreas and M{\"u}ller, Rolf and Guzman, Carlos A and Kaderali, Lars and Randall, Glenn and Meuleman, Philip and Ploss, Alexander and Pietschmann, Thomas},
  issn         = {0270-9139},
  journal      = {HEPATOLOGY},
  keyword      = {CALCIUM CHANNELS,E2 ENVELOPE GLYCOPROTEINS,LIFE-CYCLE,ENTRY,INFECTION,NEUROLEPTICS,INHIBITION,ACTIVATION,THERAPIES,REGIONS},
  language     = {eng},
  number       = {1},
  pages        = {49--62},
  title        = {Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1},
  url          = {http://dx.doi.org/10.1002/hep.28111},
  volume       = {63},
  year         = {2016},
}

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