Synthesis/biological evaluation of hydroxamic acids and their prodrugs as inhibitors for Botulinum neurotoxin A light chain |
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| Affiliation: | 1. 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;2. Department of Bacteriology, University of Wisconsin, 1550 Linden Drive, Madison, WI 53706, United States;3. 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;4. Worm Institute for Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States;1. School of Engineering and Technology, China University of Geosciences, Beijing 100083, China;2. Key Laboratory on Deep GeoDrilling Technology, Ministry of Land and Resources, China University of Geosciences, Beijing 100083, China;1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;2. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;3. Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;4. Department of Pathology and Laboratory Medicine, Children''s Hospital of Philadelphia, Philadelphia, PA;5. Department of Pediatrics, Children''s Hospital of Philadelphia, Philadelphia, PA;6. Institute of Medical Biology, Polish Academy of Science, Lodz, Poland |
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| 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. |
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| Keywords: | Botulinum neurotoxin SNARE SNAP-25 Protease inhibitor Zinc-dependent metalloprotease Hydroxamic acid Carbamate prodrug |
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