TY  - THES
T1  - Synthesis and evaluation of hepatitis C antivirals : viral E2 glycoprotein / human CD81 receptor interaction inhibitors
A1  - Holzer,Marcel
Y1  - 2008/07/23
N2  - The aim of the present work was to prepare compounds which inhibit the CD81-LEL—HCV-E2 interaction by binding to CD81-LEL. 
Starting point was a virtual screening using the open conformation of the LEL followed by synthesis and biological validation by means of an antibody neutralization assay. This showed benzyl salicylate to be moderately active with an inhibition of 25 % at 50 µM. Furthermore a biological screening revealed terfenadine to be a moderate inhibitor of the CD81-LEL—HCV-E2 interaction (27 % at 50 µM) as well. 
These two hits served as lead structures for further syntheses to increase inhibitory potency. Concerning benzyl salicylate 48 compounds with diverse substitution patterns were prepared. The synthesized compounds showed no increased inhibitory potency compared to benzyl salicylate.
For the derivatization of terfenadine 63 compounds with different structural modifications were synthesized. Their biological activity clearly demonstrates that a bulky substitution pattern at both parts of the molecule is necessary for activity as well as an H-bond acceptor at the alkyl linker. The most active compound in this series of derivatives showed an inhibition of 69 % at 50 µM.
Additional experiments with the terfenadine derivatives using viral particles revealed that there might be additional HCV infection reducing mechanisms which remain to be elucidated.
KW  - Hepatitis-C-Virus
KW  - Glykoproteine
KW  - Protein-Protein-Wechselwirkung
KW  - Inhibitor
KW  - Virusrezeptor
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2008/1645
ER  -