title: Development of potent inhibitors of botulinum neurotoxin type B.
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, causing the syndrome of botulism characterized by a flaccid paralysis. There is a great interest in designing 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 the S(1) subsite specificity, using several beta-amino thiols, has shown that this subsite prefers a p-carboxybenzyl moiety. The specificity of the S(1)' and S(2)' subsites was studied using two libraries of pseudotripeptides containing the S(1) synthon derived from the best beta-amino thiol tested. Finally, a selection of various non natural amino acids for the recognition of the "prime" domain led to the most potent inhibitor of BoNT/B described to date with a K(i) value of 20 nM.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, INSERM U266--CNRS FRE2463, UFR des Sciences Pharmaceutiques et Biologiques 4, Avenue de l'Observatoire--75270 Paris Cedex 06, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Anne
authors.forename: Serge
authors.initials: S
authors.lastname: Turcaud
authors.forename: Jean
authors.initials: J
authors.lastname: Quancard
authors.forename: Franck
authors.initials: F
authors.lastname: Teffo
authors.forename: Hervé
authors.initials: H
authors.lastname: Meudal
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019274:Botulinum Toxins, Type A; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds
chemical_list: C478620:4-(2-amino-3-((1-(2-benzo(b)thiophen-3-yl)-1-(benzylcarbamoyl)ethylcarbamoyl-2-(biphenyl-4-yl)ethylcarbamoyl)-3-sulfanylpropyl))benzoic acid; D001565:Benzoates; D009842:Oligopeptides; D011480:Protease Inhibitors; D013457:Sulfur Compounds; C096323:rimabotulinumtoxinB; D008666:Metalloendopeptidases; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A