Abstract
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Allosteric Regulation
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacology
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Binding Sites
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Computer Simulation
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Hepacivirus / enzymology*
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Quinolones / chemical synthesis
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Quinolones / chemistry*
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Quinolones / pharmacology
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Quinolones
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus