title: Synthesis/biological evaluation of hydroxamic acids and their prodrugs as inhibitors for Botulinum neurotoxin A light chain.
abstract: Botulinum neurotoxin A (BoNT/A) is the most potent toxin known. Unfortunately, it is also a potential bioweapon in terrorism, which is without an approved therapeutic treatment once cellular intoxication takes place. Previously, we reported how hydroxamic acid prodrug carbamates increased cellular uptake, which translated to successful inhibition of this neurotoxin. Building upon this research, we detail BoNT/A protease molecular modeling studies accompanied by the construction of small library of hydroxamic acids based on 2,4-dichlorocinnamic hydroxamic acid scaffold and their carbamate prodrug derivatization along with the evaluation of these molecules in both enzymatic and cellular models.
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
authors.forename: Hajime
authors.initials: H
authors.lastname: Seki
authors.affiliation: Department of Bacteriology, University of Wisconsin, 1550 Linden Drive, Madison, WI 53706, United States.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pellett
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Silhár
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
authors.forename: G Neil
authors.initials: GN
authors.lastname: Stowe
authors.affiliation: Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Blanco
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lardy
authors.affiliation: Department of Bacteriology, University of Wisconsin, 1550 Linden Drive, Madison, WI 53706, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Johnson
authors.affiliation: Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States; Worm Institute for Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States. Electronic address: kdjanda@scripps.edu.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D060326:Chemistry Techniques, Synthetic; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D006877:Hydroxamic Acids; D011355:Prodrugs; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D019274:Botulinum Toxins, Type A
keywords: Botulinum neurotoxin; Carbamate prodrug; Hydroxamic acid; Protease inhibitor; SNAP-25; SNARE; Zinc-dependent metalloprotease