Identification of Terfenadine as an Inhibitor of HumanCD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization

Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butyl-phenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27 % inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to 3g, identfied as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms.