Abstract
Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Allosteric Site
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Avian Myeloblastosis Virus / enzymology
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Binding Sites
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Crystallography, X-Ray
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DNA-Directed RNA Polymerases / antagonists & inhibitors*
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DNA-Directed RNA Polymerases / chemistry*
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Diarrhea Viruses, Bovine Viral / enzymology
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Models, Molecular*
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Protein Conformation
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiones / chemical synthesis*
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Thiones / chemistry
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / chemistry*
Substances
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Reverse Transcriptase Inhibitors
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Thiazoles
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Thiones
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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DNA-Directed RNA Polymerases