Journal ArticleDOI
Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding site
Ariamala Gopalsamy,Rajiv Chopra,Kitae Lim,Gregory Ciszewski,Mengxiao Shi,Kevin J. Curran,Steven F. Sukits,Kristine Svenson,Joel Bard,John W. Ellingboe,Atul Agarwal,Girija Krishnamurthy,Anita Y. M. Howe,Mark Orlowski,Boris Feld,John O'Connell,Tarek S. Mansour +16 more
TLDR
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor and optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity.Abstract:
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.read more
Citations
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Journal ArticleDOI
Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase
Book ChapterDOI
Structure-Function Relationships Among RNA-Dependent RNA Polymerases
TL;DR: The crystallographic, biochemical, and molecular genetic data available for viral RdRPs that have led to a detailed description of substrate and cofactor binding, fidelity of nucleotide selection and incorporation, and catalysis are reviewed.
Journal ArticleDOI
Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance
TL;DR: Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection.
Journal ArticleDOI
3D QSAR and molecular docking studies of benzimidazole derivatives as hepatitis C virus NS5B polymerase inhibitors.
TL;DR: The present 3D QSAR models were found to accurately predict the HCV NS5B polymerase inhibitory activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the benzimidazole derivatives in the data set.
Journal ArticleDOI
Binding-Site Identification and Genotypic Profiling of Hepatitis C Virus Polymerase Inhibitors
Frederik Pauwels,Wendy Mostmans,Ludo Maria Marcel Quirynen,Liesbet van der Helm,Carlo Boutton,Anne-Stéphanie Rueff,Erna Cleiren,Pierre Raboisson,Dominique Louis Nestor Ghislain Surleraux,Origène Nyanguile,Kenneth Simmen +10 more
TL;DR: A hepatitis C virus mutant and genotypic recombinant polymerase panel is established as a means of guiding medicinal chemistry through the elucidation of the site of action of novel inhibitors and profiling against genotypes.
References
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Journal ArticleDOI
Control of hepatitis C: a medicinal chemistry perspective.
Journal ArticleDOI
Sensitivity of NS3 Serine Proteases from Hepatitis C Virus Genotypes 2 and 3 to the Inhibitor BILN 2061
Diane Thibeault,Christiane Bousquet,Rock Gingras,Lisette Lagacé,Roger Maurice,Peter W. White,Daniel Lamarre +6 more
TL;DR: In vitro potency, in conjunction with the good pharmacokinetic data reported for humans, suggests that there is potential for BILN 2061 as an antiviral agent for individuals infected with non-genotype-1 HCV.
Journal ArticleDOI
Therapies for Hepatitis C Infection: Targeting the Non-Structural Proteins of HCV
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