Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: synthesis and structure optimization |
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Authors: | Holzer Marcel Ziegler Sigrid Albrecht Beatrice Kronenberger Bernd Kaul Artur Bartenschlager Ralf Kattner Lars Klein Christian D Hartmann Rolf W |
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Institution: | Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany. |
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Abstract: | Terfenadine (4-4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-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 ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to 3g, identified as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms. |
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