Abstract
A series of substrate analogue inhibitors of the serine protease HAT, containing a 4-amidinobenzylamide moiety as the P1 residue, was prepared. The most potent compounds possess a basic amino acid in the d-configuration as P3 residue. Whereas inhibitor 4 (K(i) 13 nM) containing proline as the P2 residue completely lacks selectivity, incorporation of norvaline leads to a potent inhibitor (15, K(i) 15 nM) with improved selectivity for HAT in comparison to the coagulation proteases thrombin and factor Xa or the fibrinolytic plasmin. Selected inhibitors were able to suppress influenza virus replication in a HAT-expressing MDCK cell model.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Amidines / chemical synthesis
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Amidines / chemistry
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Amidines / pharmacology*
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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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Benzyl Compounds / chemical synthesis
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Benzyl Compounds / chemistry
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Benzyl Compounds / pharmacology*
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Cells, Cultured
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Dipeptides / chemical synthesis
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Dipeptides / chemistry
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Dipeptides / pharmacology*
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Dose-Response Relationship, Drug
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Humans
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Microbial Sensitivity Tests
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Molecular Structure
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Orthomyxoviridae / drug effects*
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Orthomyxoviridae / genetics
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Serine Endopeptidases / metabolism*
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Serine Proteinase Inhibitors / chemical synthesis
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Substrate Specificity
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Virus Replication / drug effects
Substances
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Amidines
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Antiviral Agents
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Benzyl Compounds
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Dipeptides
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Serine Proteinase Inhibitors
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trypsin-like serine protease
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Serine Endopeptidases