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• W2014688619 endingPage "e10129" @default.
• W2014688619 startingPage "e10129" @default.
• W2014688619 abstract "Botulinum neurotoxin serotype A (BoNTA) causes a life-threatening neuroparalytic disease known as botulism that could afflict large, unprotected populations if the toxin were employed in an act of bioterrorism. Current post-exposure therapy is limited to symptomatic treatment or passive immunization that is effective for treating infant botulism at a cost of US $45,300 per treatment regimen. Antibodies can neutralize the extracellular but not the intracellular BoNTA. Moreover, antibody production, storage, and administration in a mass casualty scenario pose logistical challenges. Alternatively, small-molecule inhibitors of BoNTA endopeptidase (BoNTAe) are sought to antagonize the extracellular or intracellular toxin. While several such molecules reportedly demonstrated efficacy in protecting cells against BoNTA, there is scant information to show that small molecules can significantly protect mammals against BoNTA. Herein we report the development of effective small-molecules BoNTAe inhibitors with promising in vivo pharmacokinetics. One such molecule has an in vivo half-life of 6.5 hours and is devoid of obvious sign of toxicity. Pre-treatment with this molecule at 2 mg/kg protected 100% and 70% of treated mice against BoNTA at 5 times of its median-lethal dose during the periods of 2 and 4 half-lives of the inhibitor, respectively. In contrast, 40% and 0% of untreated mice survived during the respective periods. Similar levels of protection were also observed with two other small molecules. These results demonstrate that small molecules can significantly protect mice against BoNTA and support the pursuit of small-molecule antagonists as a cost-effective alternative or as an adjunct to passive immunity for treating botulism." @default.
• W2014688619 created "2016-06-24" @default.
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• W2014688619 date "2010-04-13" @default.
• W2014688619 modified "2023-09-25" @default.
• W2014688619 title "Small Molecules Showing Significant Protection of Mice against Botulinum Neurotoxin Serotype A" @default.
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• W2014688619 doi "https://doi.org/10.1371/journal.pone.0010129" @default.
• W2014688619 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2854131" @default.
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