Partial protection against Botulinum B neurotoxin-induced blocking of exocytosis by a potent inhibitor of its metallopeptidase activity.
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.
Anne
Christine
C
Département de Pharmacochimie Moléculaire et Structurale, INSERM U266/CNRS FRE2463, UFR des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.
Turcaud
Serge
S
Blommaert
Armand G S
AG
Darchen
François
F
Johnson
Eric A
EA
Roques
Bernard P
BP
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019274:Botulinum Toxins, Type A; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050683:R-SNARE Proteins; D051381:Rats; D012995:Solubility; D013574:Synaptosomes / Q000201:enzymology / Q000378:metabolism
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D050683:R-SNARE Proteins; C096323:rimabotulinumtoxinB; D045726:Metalloproteases; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A