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Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity
Author(s) -
Adler Michael,
Nicholson James D.,
Hackley Brennie E.
Publication year - 1998
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(98)00492-x
Subject(s) - botulinum neurotoxin , metalloproteinase , neurotoxin , chemistry , pharmacology , biochemistry , enzyme , medicine , toxin
The novel inhibitor 7‐ N ‐phenylcarbamoylamino‐4‐chloro‐3‐propyloxyisocoumarin (ICD 1578) was tested for its ability to antagonize the zinc metalloprotease activity of botulinum toxin B (BoNT/B). The efficacy of this compound was tested in a cell‐free system using a 50‐mer synaptobrevin peptide as substrate. The peptide, designated as [Pya 88 ] S 39–88, had a fluorescent amino acid analog, l ‐pyrenylalanine (Pya), substituted for the normal Phe 88 of synaptobrevin‐2. Cleavage by BoNT light chain yielded fragments of 38 and 11 amino acids, respectively. The smaller fragment, containing the Pya fluorophore, was readily separated and quantified by fluorescence spectroscopy at 377 nm. In the presence of 7–200 μM ICD 1578, cleavage of [Pya 88 ] S 39–88 was progressively reduced (IC 50 =27.6 μM), and 100 μM ICD 1578 produced >95% inhibition. For comparison, captopril, a well‐known zinc metalloprotease inhibitor, generated less than 10% inhibition at a concentration of 5 mM. ICD 1578 is the most potent antagonist of BoNT/B light chain thus far described.