Beta-amino-thiols inhibit the zinc metallopeptidase activity of tetanus toxin light chain.
Tetanus neurotoxin is a 150-kDa protein produced by Clostridium tetani, which causes the lethal spastic paralytic syndromes of tetanus by blocking inhibitory neurotransmitter release at central synapses. The toxin light chain (50 kDa) has a zinc endopeptidase activity specific for synaptobrevin, an essential component of the neuroexocytosis apparatus. Previous unsuccessful attempts to block the proteolytic activity of this neurotoxin with well-known inhibitors of other zinc proteases led us to study the design of specific inhibitors as a possible drug therapy to prevent the progressive evolution of tetanus following infection. Starting from the synaptobrevin sequence at the level of the cleavage site by tetanus neurotoxin (Gln76-Phe77), a thiol analogue of glutamine demonstrated inhibitory activities in the millimolar range. A structure-activity relationship performed with this compound led us to determine the requirement for the correct positioning of the thiol group, the primary amino group, and a carboxamide or sulfonamide group on the side chain. This resulted in the design of a beta-amino-(4-sulfamoylphenyl)glycine-thiol, the first significantly efficient inhibitor of tetanus neurotoxin with a Ki value of 35 +/- 5 microM.
Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM, URA D1500 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France.
L
L
Martin
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Cornille
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P
Coric
B P
BP
Roques
M C
MC
Fournié-Zaluski
D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D050683:R-SNARE Proteins; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013744:Tetanus Toxin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015032:Zinc / Q000378:metabolism*; D000096926:Benzenesulfonamides
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D008666:Metalloendopeptidases; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D013744:Tetanus Toxin; D015032:Zinc; C114190:3-(2-amino-1-sulfanylethyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C093556:zinc-endopeptidase, tetanus neurotoxin