Abstract
To explore mechanisms of hepatitis
C virus (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 cost-effective
component of HCV combination therapies
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