Abstract
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
MeSH terms
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacology*
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Edetic Acid
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Hepacivirus / enzymology*
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Indicators and Reagents
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Peptides / chemical synthesis
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Peptides / pharmacology
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RNA, Viral / chemistry
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RNA, Viral / genetics
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Zinc / pharmacology
Substances
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Benzimidazoles
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Indicators and Reagents
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NS3 protein, hepatitis C virus
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NS4 protein, hepatitis C virus
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Peptides
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RNA, Viral
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins
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Edetic Acid
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Zinc