Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: synthesis and structure optimization.
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.
Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany.
Marcel
M
Holzer
Sigrid
S
Ziegler
Beatrice
B
Albrecht
Bernd
B
Kronenberger
Artur
A
Kaul
Ralf
R
Bartenschlager
Lars
L
Kattner
Christian D
CD
Klein
Rolf W
RW
Hartmann
D000215:Acylation / Q000187:drug effects; D000914:Antibodies, Viral; D015703:Antigens, CD / Q000378:metabolism*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009500:Neutralization Tests; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D016593:Terfenadine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014771:Virion / Q000187:drug effects
D000914:Antibodies, Viral; D015703:Antigens, CD; D000998:Antiviral Agents; C554798:CD81 protein, human; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D016593:Terfenadine