Article Dans Une Revue Journal of Medicinal Chemistry Année : 2011

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

Résumé

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.

Fichier principal
Vignette du fichier
inserm-00618322_edited.pdf (703.91 Ko) Télécharger le fichier
Manuscript_Aurones-NS5B.pdf (682.5 Ko) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)
Licence
Origine Fichiers produits par l'(les) auteur(s)
Licence
Loading...

Dates et versions

inserm-00618322 , version 1 (01-09-2012)

Licence

Identifiants

Citer

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, 2011, 54 (15), pp.5395-5402. ⟨10.1021/jm200242p⟩. ⟨inserm-00618322⟩
451 Consultations
1128 Téléchargements

Altmetric

Partager

  • More