| Abstract
| - Botulinum neurotoxins are the most potent toxins known to date. They are zinc-metalloproteases able to cleave selectively an essential component of neurotransmitter exocytosis, causingthe syndrome of botulism characterized by a flaccid paralysis. There is a great interest indesigning antagonists of the action of these toxins. One way is to inhibit their catalytic activity.In this study, we report the design of such inhibitors directed toward BoNT/B. A study of theS1 subsite specificity, using several β-amino thiols, has shown that this subsite prefers ap-carboxybenzyl moiety. The specificity of the S1‘ and S2‘ subsites was studied using two librariesof pseudotripeptides containing the S1 synthon derived from the best β-amino thiol tested.Finally, a selection of various non natural amino acids for the recognition of the “prime” domainled to the most potent inhibitor of BoNT/B described to date with a Ki value of 20 nM.
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