A Platform Stratifying a Sequestering Agent and a Pharmacological Antagonist as a Means to Negate Botulinum Neurotoxicity

Harris, Tyler; Lowery, Colin A.; Hixon, Mark S.; Janda, Kim D.

doi:10.1021/cn500135h

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…This pharmacological activity coupled with an absence of detectable brain exposure hypothetically results from reduced lipophilicity and an increased propensity to hydrogen bond, resulting from the addition of a third amine. In addition to reporting 3,4-DAP analogues with improved safety profiles, we investigated carbamate, amide, and amino acid prodrugs of 3,4-DAP. , Prodrugs of 3,4-DAP would allow localized enhancement of acetylcholine release at intoxicated neuromuscular junctions without BBB penetration. Despite our efforts, optimization of 3,4-DAP prodrugs is still required for successful in vivo translation.…”

Section: Inhibitors With Unique Mechanisms Of Actionmentioning

confidence: 99%

“…In addition to reporting 3,4-DAP analogues with improved safety profiles, we investigated carbamate, amide, and amino acid prodrugs of 3,4-DAP. 57,58 Prodrugs of 3,4-DAP would allow localized enhancement of acetylcholine release at intoxicated neuromuscular junctions without BBB penetration. Despite our efforts, optimization of 3,4-DAP prodrugs is still required for successful in vivo translation.…”

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

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Strategies to Counteract Botulinum Neurotoxin A: Nature’s Deadliest Biomolecule

et al. 2019

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Conspectus Botulinum neurotoxin serotype A (BoNT/A), marketed commercially as Botox, is the most toxic substance known to man with an estimated intravenous lethal dose (LD50) of 1–2 ng/kg in humans. Despite its widespread use in cosmetic and medicinal applications, no postexposure therapeutics are available for the reversal of intoxication in the event of medical malpractice or bioterrorism. Accordingly, the Centers for Disease Control and Prevention categorizes BoNT/A as a Category A pathogen, posing the highest risk to national security and public health as a result of the ease with which BoNT/A can be weaponized and disseminated. BoNT/A-mediated lethality results from neurons impeded from releasing acetylcholine, which ultimately causes muscle paralysis and possible death by asphyxiation with the loss of diaphragm function. Currently, the only available respite for BoNT/A poisoning is antibody-based therapy; however, this intervention is only effective within 12–24 h postexposure. Small molecule therapeutics remain the only opportunity to reverse BoNT/A intoxication after neuronal poisoning and are urgently needed. Nevertheless, no small molecule BoNT/A inhibitors have reached the clinic or even advanced to clinical trials. This Account highlights the accomplishments and existing challenges facing BoNT/A drug discovery today. Using the comprehensive body of work from our laboratory, we illustrate our nearly two-decade endeavor to discover a clinically relevant BoNT/A inhibitor. Specifically, a discussion on the identification and characterization of new chemical leads, the development of in vitro and in vivo assays, and pertinent discoveries in BoNT/A structural biology related to small molecule inhibition is presented. Lead discovery efforts in our laboratory have leveraged both in vitro high-throughput screening and rational design, and an array of mechanistic strategies for inhibiting BoNT/A has been discovered, including noncovalent inhibition, metal-binding active site inhibition, covalent inhibition, and α- and β-exosite inhibition. We contrast the strengths and weaknesses of each of these mechanistic strategies and propose the most favorable approach for success. Finally, we discuss multiple serendipitous discoveries of antibotulism small molecules with alternative mechanisms of action. Remaining challenges facing clinically relevant BoNT/A inhibition are presented and analyzed, including the current inability to reconcile toxin half-life (months to greater than one year) in neurons with in vivo pharmaceutical lifetimes and reoccurring inconsistencies between in vitro, cellular, and in vivo translation. Our Account of BoNT/A chemical research emphasizes the present accomplishments and critically analyzes the remaining obstacles for drug discovery. Importantly, we call for an increased focus on the discovery of safe and effective covalent inhibitors of BoNT/A that compete with the inherent half-life of the toxin.

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Section: Inhibitors With Unique Mechanisms Of Actionmentioning

confidence: 99%

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

Strategies to Counteract Botulinum Neurotoxin A: Nature’s Deadliest Biomolecule

et al. 2019

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“…Previous studies indicate that 10-15 mM 3,4-DAP in circulation is required per hour for potassium channel blockade and acetylcholine release at the synapse. 19 Using the improved formulation, 3,4-DAP remains above this threshold concentration for over three hours after oral administration; in contrast, due to seizure activity at and above 10 mg kg À1 dosing, this concentration cannot be safely and sustainably achieved with immediaterelease formulations of 3,4-DAP.…”

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confidence: 99%

Lycopodium clavatum exine microcapsules enable safe oral delivery of 3,4-diaminopyridine for treatment of botulinum neurotoxin A intoxication

et al. 2016

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3,4-Diaminopyridine has shown promise in reversing botulinum intoxication, but poor pharmacokinetics and a narrow therapeutic window limit its clinical utility. Thus, we developed a pH-dependent oral delivery platform using club moss spore exines. These exine microcapsules slowed 3,4-diaminopyridine absorption, limited its seizure activity, and enabled delivery of doses which prolonged mouse survival after botulism neurotoxin A intoxication.

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Challenges in searching for therapeutics against Botulinum Neurotoxins

Pirazzini

Rossetto

2017

Expert Opinion on Drug Discovery

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Botulinum neurotoxins (BoNTs) are the most potent toxins known. BoNTs are responsible for botulism, a deadly neuroparalytic syndrome caused by the inactivation of neurotransmitter release at peripheral nerve terminals. Thanks to their specificity and potency, BoNTs are both considered potential bio-weapons and therapeutics of choice for a variety of medical syndromes. Several variants of BoNTs have been identified with individual biological properties and little antigenic relation. This expands greatly the potential of BoNTs as therapeutics but poses a major safety problem, increasing the need for finding appropriate antidotes. Areas covered: The authors describe the multi-step molecular mechanism through which BoNTs enter nerve terminals and discuss the many levels at which the toxins can be inhibited. They review the outcomes of the different strategies adopted to limit neurotoxicity and counter intoxication. Potential new targets arising from the last discoveries of the mechanism of action and the approaches to promote neuromuscular junction recovery are also discussed. Expert opinion: Current drug discovery efforts have mainly focused on BoNT type A and addressed primarily light chain proteolytic activity. Development of pan-BoNT inhibitors acting independently of BoNT immunological properties and targeting a common step of the intoxication process should be encouraged.

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A Platform Stratifying a Sequestering Agent and a Pharmacological Antagonist as a Means to Negate Botulinum Neurotoxicity

Cited by 4 publications

References 19 publications

Strategies to Counteract Botulinum Neurotoxin A: Nature’s Deadliest Biomolecule

Strategies to Counteract Botulinum Neurotoxin A: Nature’s Deadliest Biomolecule

Lycopodium clavatum exine microcapsules enable safe oral delivery of 3,4-diaminopyridine for treatment of botulinum neurotoxin A intoxication

Challenges in searching for therapeutics against Botulinum Neurotoxins

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