Partial Protection against Botulinum B Neurotoxin-Induced Blocking of Exocytosis by a Potent Inhibitor of Its Metallopeptidase Activity

• Published in: Chembiochem : a European journal of chemical biology Vol. 6; no. 8; pp. 1375 - 1380
• Main Authors: Anne, Christine, Turcaud, Serge, Blommaert, Armand G.S, Darchen, François, Johnson, Eric A, Roques, Bernard P
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 05-08-2005; WILEY-VCH Verlag; WILEY‐VCH Verlag
• Subjects: Animals; Binding Sites - drug effects; Botulinum Toxins - antagonists & inhibitors; Botulinum Toxins - metabolism; Botulinum Toxins, Type A; botulism; Clostridium botulinum; endopeptidase; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; exocytosis; Exocytosis - drug effects; inhibitors; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Metalloproteases - antagonists & inhibitors; Metalloproteases - metabolism; metalloproteins; R-SNARE Proteins; Rats; Solubility; Synaptosomes - enzymology; Synaptosomes - metabolism
• ISSN: 1439-4227; 1439-7633; 1439-4227
• DOI: 10.1002/cbic.200400398

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.