Time-dependent botulinum neurotoxin serotype A metalloprotease inhibitors |
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Authors: | Li Bing Cardinale Steven C Butler Michelle M Pai Ramdas Nuss Jonathan E Peet Norton P Bavari Sina Bowlin Terry L |
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Institution: | aMicrobiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA;bUnited States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA |
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Abstract: | Botulinum neurotoxins (BoNTs) are the most lethal of biological substances, and are categorized as class A biothreat agents by the Centers for Disease Control and Prevention. There are currently no drugs to treat the deadly flaccid paralysis resulting from BoNT intoxication. Among the seven BoNT serotypes, the development of therapeutics to counter BoNT/A is a priority (due to its long half-life in the neuronal cytosol and its ease of production). In this regard, the BoNT/A enzyme light chain (LC) component, a zinc metalloprotease responsible for the intracellular cleavage of synaptosomal-associated protein of 25 kDa, is a desirable target for developing post-BoNT/A intoxication rescue therapeutics. In an earlier study, we reported the high throughput screening of a library containing 70,000 compounds, and uncovered a novel class of benzimidazole acrylonitrile-based BoNT/A LC inhibitors. Herein, we present both structure–activity relationships and a proposed mechanism of action for this novel inhibitor chemotype. |
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Keywords: | Botulinum neurotoxin serotype A Benzimidazole acrylonitrile Structure&ndash activity relationships Molecular modeling Time-dependent inhibition |
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