Abstract
Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / pharmacokinetics*
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Binding Sites
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Cell Line
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Crystallography, X-Ray
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Drug Design
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hydrogen Bonding
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Mice
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Microbial Sensitivity Tests
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Oligopeptides / antagonists & inhibitors
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / pharmacokinetics*
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Virus Replication / drug effects*
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Virus Replication / physiology
Substances
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Antiviral Agents
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NS3 protein, hepatitis C virus
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NS4 protein, hepatitis C virus
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Oligopeptides
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Protease Inhibitors
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Viral Nonstructural Proteins