Non-Nucleoside Benzimidazole-Based Allosteric Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Inhibition of Subgenomic Hepatitis C Virus RNA Replicons in Huh-7 Cells

2004 ◽  
Vol 47 (27) ◽  
pp. 6884-6892 ◽  
Author(s):  
Pierre L. Beaulieu ◽  
Yves Bousquet ◽  
Jean Gauthier ◽  
James Gillard ◽  
Martin Marquis ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Virus Rna ◽  
Ns5b Polymerase

Potent Inhibitors of Subgenomic Hepatitis C Virus RNA Replication through Optimization of Indole-N-Acetamide Allosteric Inhibitors of the Viral NS5B Polymerase

2005 ◽  
Vol 48 (14) ◽  
pp. 4547-4557 ◽  
Author(s):  
Steven Harper ◽  
Salvatore Avolio ◽  
Barbara Pacini ◽  
Marcello Di Filippo ◽  
Sergio Altamura ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Replication ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Virus Rna ◽  
Ns5b Polymerase

B-ring modified aurones as promising allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase

2014 ◽  
Vol 80 ◽  
pp. 579-592 ◽  
Author(s):  
Amel Meguellati ◽  
Abdelhakim Ahmed-Belkacem ◽  
Wei Yi ◽  
Romain Haudecoeur ◽  
Marie Crouillère ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Rna Dependent Rna Polymerase ◽  
Virus Rna

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

2011 ◽  
Vol 54 (15) ◽  
pp. 5395-5402 ◽  
Author(s):  
Romain Haudecoeur ◽  
Abdelhakim Ahmed-Belkacem ◽  
Wei Yi ◽  
Antoine Fortuné ◽  
Rozenn Brillet ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Rna Dependent Rna Polymerase ◽  
Naturally Occurring ◽  
Virus Rna

scholarly journals Mechanismof Action and Antiviral Activity of Benzimidazole-Based AllostericInhibitors of the Hepatitis C Virus RNA-Dependent RNAPolymerase

2003 ◽  
Vol 77 (24) ◽  
pp. 13225-13231 ◽  
Author(s):  
Licia Tomei ◽  
Sergio Altamura ◽  
Linda Bartholomew ◽  
Antonino Biroccio ◽  
Alessandra Ceccacci ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hcv Rna ◽  
Allosteric Site ◽  
Hepatitis C Virus Rna ◽  
Rna Amplification ◽  
Allosteric Inhibitors ◽  
Virus Rna ◽  
Elongation Step ◽  
Further Development

ABSTRACT The RNA-dependent RNA polymerase of hepatitis C virus (HCV) is the catalytic subunit of the viral RNA amplification machinery and is an appealing target for the development of new therapeutic agents against HCV infection. Nonnucleoside inhibitors based on a benzimidazole scaffold have been recently reported. Compounds of this class are efficient inhibitors of HCV RNA replication in cell culture, thus providing attractive candidates for further development. Here we report the detailed analysis of the mechanism of action of selected benzimidazole inhibitors. Kinetic data and binding experiments indicated that these compounds act as allosteric inhibitors that block the activity of the polymerase prior to the elongation step. Escape mutations that confer resistance to these compounds map to proline 495, a residue located on the surface of the polymerase thumb domain and away from the active site. Substitution of this residue is sufficient to make the HCV enzyme and replicons resistant to the inhibitors. Interestingly, proline 495 lies in a recently identified noncatalytic GTP-binding site, thus validating it as a potential allosteric site that can be targeted by small-molecule inhibitors of HCV polymerase.

scholarly journals Inhibition of the Subgenomic Hepatitis C Virus Replicon in Huh-7 Cells by 2′-Deoxy-2′-Fluorocytidine

2004 ◽  
Vol 48 (2) ◽  
pp. 651-654 ◽  
Author(s):  
Lieven J. Stuyver ◽  
Tamara R. McBrayer ◽  
Tony Whitaker ◽  
Phillip M. Tharnish ◽  
Mangala Ramesh ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Potent Inhibitor ◽  
Hepatitis C Virus Rna ◽  
Phase Arrest ◽  
Virus Rna ◽  
Cellular Target ◽  
Viral Target ◽  
Rna Replicon ◽  
Ns5b Polymerase

ABSTRACT 2′-Deoxy-2′-fluorocytidine (FdC) is a potent inhibitor of the hepatitis C virus RNA replicon in culture, and FdC-5′-triphosphate is an effective inhibitor of the NS5B polymerase. Dynamic profiling of cell growth in an antiviral assay showed that FdC caused cytostasis due to an S-phase arrest. These observations demonstrate that FdC treatment is affecting both a viral target and a cellular target.

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