title: 8-Hydroxyquinoline and hydroxamic acid inhibitors of botulinum neurotoxin BoNT/A.
abstract: We describe here the state of the art of certain aspects concerning potential small molecule therapy directed toward botulism, by inhibition of the zinc-protease containing light chain (LC) of botulinum neurotoxin BoNT/A from the anaerobic bacillus Clostridium botulinum. Botulinum neurotoxins (BoNTs) are comprised of eight serologically-distinct proteins (A - H), several of which are further divided, such as BoNT/A which has five subtypes. The BoNTs are the most toxic substances known to mankind, causing a form of flaccid paralysis that can be rapid and is often lethal. BoNT/A is comprised of a ~100 kDa heavy chain (HC) attached via a single disulfide Cys-Cys bond to a ~50 kDa LC. The HC mediates transport to and uptake by presynaptic glutamatergic neurons, where the LC cleaves the protein SNAP-25 and thus prevents vesicular trafficking and release of acetylcholine. The Zn-endoprotease activity of the LC of BoNT/A is a target for the development of small molecule inhibitors of BoNT/A-mediated toxicity. A variety of BoNT/A LC inhibitors have been described to date and we focus here primarily on the Zn-binding 8-hydroxyquinoline structural type as well as some of the previously-described hydroxamic acids.
authors.forename: Tobin J
authors.initials: TJ
authors.lastname: Dickerson
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Pelletier
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, USA. areitz@fc-cdci.com.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology*; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D001906:Botulism / Q000188:drug therapy / Q000473:pathology; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D003014:Clostridium botulinum / Q000472:pathogenicity / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology*; D010243:Paralysis / Q000188:drug therapy / Q000473:pathology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D000931:Antidotes; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D054852:Small Molecule Libraries; D015125:Oxyquinoline; D019274:Botulinum Toxins, Type A; D015032:Zinc