Beta-amino-thiols inhibit the zinc metallopeptidase activity of tetanus toxin light chain.

Abstract

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.

• Authors: L Martin, F Cornille, P Coric, B P Roques, M C Fournié-Zaluski
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 41 Issue 18 Pg. 3450-60 (Aug 27 1998) ISSN: 0022-2623 [Print] United States
• PMID: 9719598 (Publication Type: Journal Article)

Chemical References

• 3-(2-amino-1-sulfanylethyl)benzenesulfonamide
• Enzyme Inhibitors
• Membrane Proteins
• Nerve Tissue Proteins
• R-SNARE Proteins
• Sulfhydryl Compounds
• Sulfonamides
• Tetanus Toxin
• Metalloendopeptidases
• zinc-endopeptidase, tetanus neurotoxin
• Zinc

Topics

• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Membrane Proteins (chemistry, metabolism)
• Metalloendopeptidases (antagonists & inhibitors, chemistry)
• Nerve Tissue Proteins (chemistry, metabolism)
• R-SNARE Proteins
• Structure-Activity Relationship
• Sulfhydryl Compounds (chemical synthesis, metabolism, pharmacology)
• Sulfonamides (chemical synthesis, metabolism, pharmacology)
• Tetanus Toxin (antagonists & inhibitors, chemistry)
• Zinc (metabolism)