title: Thio-derived disulfides as potent inhibitors of botulinum neurotoxin type B: implications for zinc interaction.
abstract: Botulinum neurotoxin type B causes the inhibition of acetylcholine release at the neuromuscular junction resulting in a flaccid paralysis designated botulism. This occurs through the cleavage of synaptobrevin, an intracellular critical component of neurotransmitter exocytosis, by the zinc-metallopeptidase activity of the smallest subunit of the toxin. Blocking the proteolytic activity may present an attractive approach to treat botulism as to date there is no efficient specific drug therapy available. We have therefore recently described a series of beta-amino-thiol derived pseudotripeptides able of inhibiting the toxin at low (10(-8) M) concentration. In this study, binding characteristics of the protein's active site are explored through various structural modifications of the thiol functionality which was supposed to be a key structural constituent for effective zinc-ion chelation. Surprisingly, sulfanyl-derivatives such as symmetric disulfides were shown to be better inhibitors than their thiol-counterparts, the most potent compound displaying a Ki value of 3.4 nM.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, UFR des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75270 Paris 06, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Anne
authors.forename: Armand
authors.initials: A
authors.lastname: Blommaert
authors.forename: Serge
authors.initials: S
authors.lastname: Turcaud
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Martin
authors.forename: Hervé
authors.initials: H
authors.lastname: Meudal
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D001665:Binding Sites; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019274:Botulinum Toxins, Type A; D002135:Calcium-Binding Proteins; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D013457:Sulfur Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D050857:Synaptotagmins; D015032:Zinc / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D004220:Disulfides; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D013457:Sulfur Compounds; C096323:rimabotulinumtoxinB; D050857:Synaptotagmins; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; D015032:Zinc