Title: Novel benzimidazole inhibitors of botulinum neurotoxin/A display enzyme and cell-based potency

Authors: Steven C. Cardinale, Michelle M. Butler, Gordon Ruthel, Jonathan E. Nuss, Laura M. Wanner, Bing Li, Ramdas P. Pai, Norton P. Peet, Sina Bavari, Terry L. Bowlin

Addresses: Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA. ' Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA. ' US Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702, USA. ' US Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702, USA. ' US Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702, USA. ' Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA. ' Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA. ' Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA. ' US Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702, USA. ' Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA

Abstract: Botulinum Neurotoxins (BoNTs) are used therapeutically and in cosmetics, providing potential for bioterrorist activity, thus driving the search for small-molecule BoNT inhibitors. This report describes a 70,000-compound screen for inhibition of BoNT/A using a FRET assay to detect proteolysis of a peptide substrate. Hits were confirmed, followed by evaluation to determine compound specificity. Inhibitors fell into three main chemical classes, and on the basis of potency and specificity of inhibition, the activities of two chemotypes were examined further. Compounds exhibited specificity for BoNT/A LC inhibition with respect to other metalloproteases and displayed activity in a neuronal assay for botulinum intoxication.

Keywords: botulinum neurotoxins; serotype A; bioterrorism; SNAP-25; high throughput screening; benzimidazole acrylonitrile; hydroxyquinoline; small molecule inhibitors; drug discovery; metalloprotease; BoNT inhibitors.

DOI: 10.1504/TBJ.2011.041813

The Botulinum Journal, 2011 Vol.2 No.1, pp.16 - 29

Published online: 06 Aug 2011 *

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