Document Detail


Mechanism of action and antiviral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
MedLine Citation:
PMID:  14645579     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Licia Tomei; Sergio Altamura; Linda Bartholomew; Antonino Biroccio; Alessandra Ceccacci; Laura Pacini; Frank Narjes; Nadia Gennari; Monica Bisbocci; Ilario Incitti; Laura Orsatti; Steven Harper; Ian Stansfield; Michael Rowley; Raffaele De Francesco; Giovanni Migliaccio
Related Documents :
12866049 - Fold recognition, homology modeling, docking simulations, kinetics analysis and mutagen...
19174549 - Two crystal structures of lysyl-trna synthetase from bacillus stearothermophilus in com...
20921269 - Long-range tertiary interactions in single hammerhead ribozymes bias motional sampling ...
10788319 - Effects of phosphorothioate modifications on precursor trna processing by eukaryotic rn...
11170439 - Effect of alanine-293 replacement on the activity, atp binding, and editing of escheric...
19092929 - Structure of an argonaute silencing complex with a seed-containing guide dna and target...
10465559 - Significant compensatory role of position y-2 conferring high affinity to non-phosphory...
25153729 - Rates of hexadehydro-diels-alder (hdda) cyclizations: impact of the linker structure.
1709939 - Vitronectin governs the interaction between plasminogen activator inhibitor 1 and tissu...
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of virology     Volume:  77     ISSN:  0022-538X     ISO Abbreviation:  J. Virol.     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-03     Completed Date:  2004-01-13     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13225-31     Citation Subset:  IM    
Affiliation:
Istituto di Ricerche di Biologia Molecolare "P. Angeletti," 00040 Pomezia-Rome, Italy. Licia_Tomei@Merck.com
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Allosteric Site / drug effects*
Antiviral Agents / pharmacology*
Benzimidazoles / pharmacology*
Cell Line
Enzyme Inhibitors / pharmacology
Hepacivirus / drug effects*,  enzymology
Humans
Kinetics
RNA Replicase / antagonists & inhibitors*,  genetics,  metabolism
RNA, Viral / metabolism
Viral Nonstructural Proteins / antagonists & inhibitors,  genetics,  metabolism
Virus Replication
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Benzimidazoles; 0/Enzyme Inhibitors; 0/NS-5 protein, hepatitis C virus; 0/RNA, Viral; 0/Viral Nonstructural Proteins; E24GX49LD8/benzimidazole; EC 2.7.7.48/RNA Replicase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Mechanisms governing maintenance of Cdk1/cyclin B1 kinase activity in cells infected with human cyto...
Next Document:  Signals that dictate nuclear localization of human papillomavirus type 16 oncoprotein E6 in living c...