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Partial Protection against Botulinum B Neurotoxin‐Induced Blocking of Exocytosis by a Potent Inhibitor of Its Metallopeptidase Activity
Author(s) -
Anne Christine,
Turcaud Serge,
Blommaert Armand G. S.,
Darchen François,
Johnson Eric A.,
Roques Bernard P.
Publication year - 2005
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200400398
Subject(s) - synaptobrevin , neurotoxin , botulism , clostridium botulinum , chemistry , exocytosis , synaptic vesicle , biochemistry , botulinum neurotoxin , toxin , enzyme , pharmacology , biology , secretion , vesicle , microbiology and biotechnology , membrane
Clostridium botulinum neurotoxins (BoNTs) cause botulism, which is characterized by a flaccid paralysis, through inhibition of acetylcholine release by peripheral cholinergic nerve terminals. This is due to the zinc metallopeptidase activity of the neurotoxin, cleaving one component (synaptobrevin for BoNT/B) of the exocytosis machinery. Yet, there are no specific agents able to control the peptidase‐related effects of BoNT/B. We recently developed the first compounds to inhibit this enzymatic activity in the nanomolar range. Here we report that two of our best inhibitors prevent the BoNT/B‐induced cleavage of native synaptobrevin on synaptic vesicles, and partially inhibit the suppression of [ 3 H]noradrenaline release from synaptosomes that is caused by BoNT/B. These results were obtained at micromolar concentrations, consistent with the measured inhibitory potency of these inhibitors on the native toxin. These compounds provide a new way to possibly prevent and/or to control the neurotoxin effects of botulinum.