title: Metallopeptidase inhibitors of tetanus toxin: A combinatorial approach.
abstract: The bacterial protein tetanus toxin (TeNt), which belongs to the family of zinc endopeptidases, cleaves synaptobrevin, an essential synaptic protein component of the neurotransmitter exocytosis apparatus, at a single peptide bond (Gln76-Phe77). This protease activity is a particularly attractive target for designing potent and selective synthetic inhibitors as a possible drug therapy for tetanus. beta-Aminothiols mimicking Gln76 of synaptobrevin have been previously shown to inhibit the tetanus neurotoxin enzymatic activity in the 35-250 microM range. These compounds have now been modified to interact with S' subsites of the TeNt active site, with the aim of increasing their inhibitory potencies. Combinatorial libraries of pseudotripeptides, containing an ethylene sulfonamide or an m-sulfonamidophenyl moiety as the P1 side chain and natural amino acids in P1' and P2' positions, were synthesized. The best inhibitory activity was observed with Tyr and His as P1' and P2' components, respectively. This led to new inhibitors of TeNt with Ki values in the 3-4 microM range. These molecules are the most potent inhibitors of TeNt described so far.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM, UMR 8600 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, 75270 Paris Cedex 06, France.
authors.forename: L
authors.initials: L
authors.lastname: Martin
authors.forename: F
authors.initials: F
authors.lastname: Cornille
authors.forename: S
authors.initials: S
authors.lastname: Turcaud
authors.forename: H
authors.initials: H
authors.lastname: Meudal
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
authors.forename: M C
authors.initials: MC
authors.lastname: Fournié-Zaluski
mesh_terms: D000595:Amino Acid Sequence; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D019151:Peptide Library; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D013744:Tetanus Toxin / Q000037:antagonists & inhibitors*