title: Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays.
abstract: Botulinum neurotoxin A (BoNT/A) is one of the most deadly toxins and is the etiological agent of the potentially fatal condition, botulism. Herein, we investigated 8-hydroxyquinoline (quinolin-8-ol) as a potential inhibitor scaffold for preventing the deadly neurochemical effects of the toxin. Quinolinols are known chelators that can disrupt the BoNT/A metalloprotease zinc-containing active site, thus impeding its proteolysis of the endogenous protein substrate, synaptosomal-associated protein 25 (SNAP-25). By use of this information, the structure-activity relationship (SAR) of the quinolinol-5-sulfonamide scaffold was explored through preparation of a crude sulfonamide library and evaluation of the library in a BoNT/A LC enzymatic assay. Potency optimization of the sulfonamide hit compounds was undertaken as informed by docking studies, granting a lead compound with a submicromolar Ki. These quinolinol analogues demonstrated inhibitory activity in a cell-based model for SNAP-25 cleavage and an ex vivo assay for BoNT/A-mediated muscle paralysis.
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Paul T
authors.identifier: 0000-0002-8357-1743
authors.initials: PT
authors.lastname: Bremer
authors.affiliation: Neurobehavioral Toxicology Branch, Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense , 2900 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Adler
authors.affiliation: Neurobehavioral Toxicology Branch, Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense , 2900 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400, United States.
authors.forename: Cecilia H
authors.initials: CH
authors.lastname: Phung
authors.affiliation: Neurobehavioral Toxicology Branch, Analytical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense , 2900 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400, United States.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Kim D
authors.identifier: 0000-0001-6759-4227
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D059748:Proteolysis; D013329:Structure-Activity Relationship
chemical_list: D006912:Hydroxyquinolines; D019274:Botulinum Toxins, Type A