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Synthesis and biological evaluation of botulinum neurotoxin a protease inhibitors.

ABSTRACT: NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.

SUBMITTER: Li B

PROVIDER: S-EPMC2841792 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Synthesis and biological evaluation of botulinum neurotoxin a protease inhibitors.

Li Bing B Pai Ramdas R Cardinale Steven C SC Butler Michelle M MM Peet Norton P NP Moir Donald T DT Bavari Sina S Bowlin Terry L TL

Journal of medicinal chemistry 20100301 5

NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of t ...[more]

PMID: 20155918

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