@article{85386,
  keywords = {Humans, Genotype, Cells, Cultured, Virus Internalization, Flunarizine, Hepacivirus, Viral Fusion Proteins},
  author = {Paula Perin and Sibylle Haid and Richard Brown and Juliane Doerrbecker and Kai Schulze and Carsten Zeilinger and von Markus Schaewen and Brigitte Heller and Koen Vercauteren and Eva Luxenburger and Yasmine Baktash and Florian Vondran and Sietkse Speerstra and Abdullah Awadh and Furkat Mukhtarov and Luis Schang and Andreas Kirschning and Rolf M{\"u}ller and Carlos Guzman and Lars Kaderali and Glenn Randall and Philip Meuleman and Alexander Ploss and Thomas Pietschmann},
  title = {Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1.},
  abstract = {<p>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.</p>
},
  year = {2016},
  journal = {Hepatology},
  volume = {63},
  pages = {49-62},
  month = {01/2016},
  issn = {1527-3350},
  doi = {10.1002/hep.28111},
  language = {eng},
}