[Tetanus and botulinum toxins are zinc metallopeptidases: molecular mechanisms and inhibition of their neurotoxicity].
The very high toxicity of tetanus neurotoxin (TeNT) and botulinum neurotoxin (BoNT) are related to their nature of zinc metallopeptidases able to selectively cleave small proteins involved in neurotransmitters exocytosis. At this time, there is no efficient and selective therapy towards tetanos and tobulism as well as protection against a possible spreading of the toxins. We have therefore investigated the minimum sequences of TeNT and BoNT substrates allowing an efficient and simple fluorescent dosage of the enzymatic activity to be developed. Using synaptobrevin (93 amino acids) as substrate of TeNT and several fragments synthesised by solid phase method, we have shown that the clostridial neurotoxins behave as allosteric-type enzymes. This is the first example in zinc metallopeptidases. Based on these results a strategy, including the use of combinatorial chemistry, was carried out issuing in the design of the first potent inhibitors of TeNT and BoNT.
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D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050683:R-SNARE Proteins; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D009435:Synaptic Transmission / Q000187:drug effects; D013744:Tetanus Toxin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc
D008565:Membrane Proteins; D010446:Peptide Fragments; D011480:Protease Inhibitors; D050683:R-SNARE Proteins; D013744:Tetanus Toxin; D008666:Metalloendopeptidases; D001905:Botulinum Toxins; D015032:Zinc