Botulinum Neurotoxin
Botulinum neurotoxins (BoNTs), the proteins that cause the disease botulism, have been heavily studied in recent years due to the dual nature of these proteins as both potent biopharmaceuticals as well as possible weapons of bioterrorism. In particular, botulinum neurotoxin serotype A (BoNT/A) is the deadliest toxin known to man with a potency 1011 times that of cyanide (LD50 ≈ 1-5 ng/kg).
Because of this risk, the CDC has classified BoNTs as ‘category A’ agents, and recent reevaluation by a U.S. Federal panel of scientists and security experts has recommended BoNT be designated a ‘Tier 1 select agent’, a category subject to the highest possible security standards. While vaccine-based therapeutics designed to counteract the extreme morbidity and mortality associated with BoNT intoxication have been reported and tested clinically, optimal efficacy using this approach is observed prior to toxin exposure, limiting the use of a vaccine primarily to prophylactic measures.
Our laboratory, as well as others, has conducted various high-throughput screens in an attempt to uncover small molecules that can reduce toxin function and/or restore native phenotypes to intoxicated cells after intoxication has occurred. Specifically, we have employed a number of techniques including FRET-based homogenous HTS assays, multiplexed cell-based reporter systems, and in vivo PK, and toxin bioassays to uncover lead molecules that potently inhibit BoNT/A or allow cells to resume normal exocytosis activity even in the face of BoNT/A exposure. Using this multi-tiered approach, molecules can be rapidly triaged for poor characteristics, whether target efficacy or DMPK properties and optimized prior to advancement into the mouse lethality bioassay.
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