Partial protection against Botulinum B neurotoxin-induced blocking of exocytosis by a potent inhibitor of its metallopeptidase activity.

Christine Anne, Serge Turcaud, Armand G S Blommaert, François Darchen, Eric A Johnson, Bernard P Roques

Département de Pharmacochimie Moléculaire et Structurale, INSERM U266/CNRS FRE2463, UFR des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.

Chembiochem : a European journal of chemical biology 2005 Aug

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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 [3H]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.

Citation

Christine Anne, Serge Turcaud, Armand G S Blommaert, François Darchen, Eric A Johnson, Bernard P Roques. Partial protection against Botulinum B neurotoxin-induced blocking of exocytosis by a potent inhibitor of its metallopeptidase activity. Chembiochem : a European journal of chemical biology. 2005 Aug;6(8):1375-80