期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 115, 期 -, 页码 217-229出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.03.005
关键词
Aurones; Hepatitis C virus; RNA-dependent RNA polymerase
资金
- ANR (Agence Nationale pour la Recherche) [ANR-11-LABX-0003-01]
- ANRS (Agence Nationale de la Recherche sur le SIDA et les Hepatites Virales)
- FRM (Fondation pour la Recherche Medicate)
The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (lC(50) = 1.3 mu M). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives. (C) 2016 Elsevier Masson SAS. All rights reserved.
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