Abstract
A new mechanistic class of BoNT/A zinc metalloprotease inhibitors, from Echinacea, exemplified by the natural product d-chicoric acid (I1) is disclosed. A detailed evaluation of chicoric acid's mechanism of inhibition reveals that the inhibitor binds to an exosite, displays noncompetitive partial inhibition, and is synergistic with a competitive active site inhibitor when used in combination. Other components found in Echinacea, I3 and I4, were also inhibitors of the protease.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Biological Factors / chemical synthesis
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Biological Factors / chemistry
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Biological Factors / pharmacology*
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Botulinum Toxins, Type A / antagonists & inhibitors*
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Botulinum Toxins, Type A / metabolism
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Caffeic Acids / chemical synthesis
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Caffeic Acids / chemistry
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Caffeic Acids / pharmacology
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Chlorogenic Acid / chemical synthesis
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Chlorogenic Acid / chemistry
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Chlorogenic Acid / pharmacology
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Clostridium botulinum / enzymology*
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Molecular Conformation
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Phenols / chemical synthesis
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Phenols / chemistry
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Phenols / pharmacology
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Succinates / chemical synthesis
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Succinates / chemistry
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Succinates / pharmacology
Substances
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Biological Factors
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Caffeic Acids
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Hydroxamic Acids
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Phenols
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Protease Inhibitors
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Succinates
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Chlorogenic Acid
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Botulinum Toxins, Type A
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chicoric acid
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caftaric acid