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Novel small molecules as potent inhibitors and tight binders of the metalloproteases in botulinum neurotoxins A and B
Author(s) -
Lai Huiguo,
Gul Nizamettin,
Roxas Virginia,
Dakshanamurthy Sivanesan,
Shah Salimuddin,
Yang David C. H.,
Smith Leonard A.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a639-b
Subject(s) - chemistry , botulism , botulinum neurotoxin , peptide , small molecule , neurotoxin , recombinant dna , exocytosis , biochemistry , toxin , secretion , biology , microbiology and biotechnology , gene
Botulinum neurotoxin (BoNT), the most lethal substance known, consists of a heavy chain (HC) and a light chain (LC). The LC specifically cleaves and inactivates the SNARE proteins, blocks neuronal exocytosis, and results in flaccid paralysis. The occurrence of multiple serotypes (A‐G) presents notable challenges to the development of therapeutics using antibodies and peptide inhibitors. We initiated a structure‐based approach to the identification of small molecule inhibitors of the proteolytic activity of BoNT. HPLC‐based assays revealed a number of compounds that reduced the activity of LC‐A or LC‐B with serotype specificity, and several inhibited LCs of both serotypes. The apparent binding constants of the inhibitors to recombinant LC‐A and LC‐B were determined using fluorescence titration. Molecular modeling of the inhibitor‐LC complexes revealed putative interactions of these compounds with the active sites of LC‐A and LC‐B. Further development of these lead inhibitors may provide effective therapeutics against botulism.