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.

• Authors: Bing Li, Ramdas Pai, Steven C Cardinale, Michelle M Butler, Norton P Peet, Donald T Moir, Sina Bavari, Terry L Bowlin
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 5 Pg. 2264-76 (Mar 11 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20155918 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amidines
• Benzimidazoles
• Indoles
• Protease Inhibitors
• Thiophenes
• Botulinum Toxins, Type A

Topics

• Amidines (chemical synthesis, chemistry, pharmacology)
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Botulinum Toxins, Type A (antagonists & inhibitors, metabolism)
• Fluorescence Resonance Energy Transfer
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Inhibitory Concentration 50
• Magnetic Resonance Spectroscopy
• Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
• Spectrometry, Mass, Electrospray Ionization
• Structure-Activity Relationship
• Thiophenes (chemical synthesis, chemistry, pharmacology)