title: Small tripeptide surrogates with low nanomolar affinity as potent inhibitors of the botulinum neurotoxin B metallo-proteolytic activity.
abstract: Botulinum neurotoxin type B is a high-weight (150 kDa) protein produced by the anaerobic bacillus Clostridium botulinum. This metallo-protease neurotoxin cleaves synaptobrevin, a protein, which is crucial to neurotransmission, resulting in the muscle paralysis, which characterizes botulism. Inhibition of the metallo-peptidase activity is a possible approach to obtain specific therapeutics to treat botulism. We have previously reported a successful attempt to block the proteolytic activity of this neurotoxin with new, selective amino-thiol inhibitors endowed with Ki values in the 15-20 nanomolar range. With the aim of increasing the affinity and bioavailability of this first series of inhibitors we have optimized the residue that fits the P(1) subsite of the enzyme by comparing a series of ligands that contain subtle but significant variants of the parent structure. In addition, this strategy provided a simplification of the synthesis of BoNT/B inhibitors by reducing the possible number of stereoisomers. As such we were able to enhance the inhibitory potency whilst reducing the size as compared to the initial privileged structure yielding the first pseudo-tripeptide inhibitors with Ki values in the low nanomolar range.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, UFR des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris cedex 06, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Blommaert
authors.forename: Serge
authors.initials: S
authors.lastname: Turcaud
authors.forename: Christine
authors.initials: C
authors.lastname: Anne
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019274:Botulinum Toxins, Type A; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; C096323:rimabotulinumtoxinB; D008666:Metalloendopeptidases; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A