Discovery of Naturally Occurring Aurones That Are Potent Allosteric Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase.

Romain Haudecoeur 1 Abdelhakim Ahmed-Belkacem 2 Wei Yi 1 Antoine Fortuné 1 Rozenn Brillet 2 Catherine Belle 3 Edwige Nicolle 1 Coralie Pallier 2, 4 Jean-Michel Pawlotsky 2, 5 Ahcène Boumendjel 1, *
* Auteur correspondant
1 DPM - Département de pharmacochimie moléculaire
2 IMRB - Institut Mondor de Recherche Biomédicale
3 DCM - Département de Chimie Moléculaire
4 Laboratoire de virologie
5 Centre National de Référence Virus des hépatites B, C et Delta
Abstract : We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 aurones was rationally explored in an enzyme assay. Molecular docking studies were used to determine how aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivatives were found to have potent inhibitory effects on HCV RdRp, with IC(50) below 5 μM and excellent selectivity index (inhibition activity versus cellular cytotoxicity). The most active aurone analogue was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6-dihydroxybenzofuran-3(2H)-one (compound 51), with an IC(50) of 2.2 μM. Their potent RdRp inhibitory activity and their low toxicity make these molecules attractive candidates as direct-acting anti-HCV agents.
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Journal of Medicinal Chemistry, American Chemical Society, 2011, 54 (15), pp.5395-5402. 〈10.1021/jm200242p〉
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Romain Haudecoeur, Abdelhakim Ahmed-Belkacem, Wei Yi, Antoine Fortuné, Rozenn Brillet, et al.. Discovery of Naturally Occurring Aurones That Are Potent Allosteric Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase.. Journal of Medicinal Chemistry, American Chemical Society, 2011, 54 (15), pp.5395-5402. 〈10.1021/jm200242p〉. 〈inserm-00618322〉

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