Chirality Holds the Key for Potent Inhibition of the Botulinum Neurotoxin Serotype A Protease

Botulinum neurotoxin serotype A (BoNT/A) is the most toxic protein known to man and also a bioterrorism agent. As defined by our previous research targeting the etiological agent responsible for BoNT/A intoxication, a protease, we now report on the asymmetric synthesis of four new BoNT/A inhibitors;...

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Bibliographic Details
Published in:Organic letters 2010-02, Vol.12 (4), p.756-759
Main Authors: Stowe, G. Neil, Šilhár, Peter, Hixon, Mark S, Silvaggi, Nicholas R, Allen, Karen N, Moe, Scott T, Jacobson, Alan R, Barbieri, Joseph T, Janda, Kim D
Format: Article
Language:English
Subjects:
Botulinum Toxins, Type A - antagonists & inhibitors
Botulinum Toxins, Type A - metabolism
Botulinum Toxins, Type A - toxicity
Catalysis
Clostridium - chemistry
Crystallography, X-Ray
Humans
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Molecular Structure
Neurotoxins - antagonists & inhibitors
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary:Botulinum neurotoxin serotype A (BoNT/A) is the most toxic protein known to man and also a bioterrorism agent. As defined by our previous research targeting the etiological agent responsible for BoNT/A intoxication, a protease, we now report on the asymmetric synthesis of four new BoNT/A inhibitors; the most potent of this series is roughly 2-fold more active than the best small molecule inhibitor currently known.
ISSN:1523-7060
1523-7052
DOI:10.1021/ol902820z