title: Time-dependent botulinum neurotoxin serotype A metalloprotease inhibitors.
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.
authors.affiliation: Microbiotix, Inc., One Innovation Drive, Worcester, MA 01605, USA. bli@microbiotix.com
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Steven C
authors.initials: SC
authors.lastname: Cardinale
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Butler
authors.forename: Ramdas
authors.initials: R
authors.lastname: Pai
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Nuss
authors.forename: Norton P
authors.initials: NP
authors.lastname: Peet
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
mesh_terms: D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001906:Botulism / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D009498:Neurotoxins; D009570:Nitriles; D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A
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