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

Molecules

Marcel Holzer³  Sigrid Ziegler³  Beatrice Albrecht³  Bernd Kronenberger³  Artur Kaul²  Ralf Bartenschlager²  Lars Kattner¹  Christian D. Klein³ 

[1]Endotherm GmbH, Science-Park II, D-66123 Saarbrücken, Germany

[2]Department of Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany

[3]Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany

关键词: Hepatitis C Virus;    CD81-receptor;    large extracellular loop;    terfenadine derivatives;    microwave assisted syntheses;   

DOI  :  10.3390/molecules13051081

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2008 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.