Persistence of Botulinum Neurotoxin Inactivation of Nerve Function

Shoemaker, Charles B.; Oyler, George A.

doi:10.1007/978-3-642-33570-9_9

Cited by 26 publications

(29 citation statements)

References 58 publications

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“…Apparently, there are enough differences between the overall three-dimensional conformation of the endogenous enzyme relative to those of the recombinant LCs that a classical developmental approach may not work. Whether this phenomenon is related to the endogenous enzyme being membrane-bound (Shoemaker and Oyler, 2013) or to post-translational modifications of the LC by host mechanisms (Ferrer-Montiel et al, 1996) remains to be established. However, caution is warranted when trying to draw too detailed of a conclusion from the SAR.…”

Section: Discussionmentioning

confidence: 99%

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

Toxicon

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Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.

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Section: Discussionmentioning

confidence: 99%

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

Toxicon

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“…It has been recently shown that BoNT/A L chain is extraordinarily stable because it escapes the action of ubiquitin ligases, by recruiting deubiquitinases, i.e. specialized enzymes that remove polyubiquitin chains (Shoemaker and Oyler, 2013;Tsai et al, 2017). No comparative studies of the toxin lifetime in the motor and in the autonomic nerve terminal are available.…”

Section: Duration Of Actionmentioning

confidence: 99%

The binding of botulinum neurotoxins to different peripheral neurons

Rossetto

2018

Toxicon

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Botulinum neurotoxins are the most potent toxins known. The double receptor binding modality represents one of the most significant properties of botulinum neurotoxins and largely accounts for their incredible potency and lethality. Despite the high affinity and the very specific binding, botulinum neurotoxins are versatile and multi-tasking toxins. Indeed they are able to act both at the somatic and at the autonomic nervous system. In spite of the preference for cholinergic nerve terminals botulinum neurotoxins have been shown to inhibit to some extent also the noradrenergic postganglionic sympathetic nerve terminals and the afferent nerve terminals of the sensory neurons inhibiting the release of neuropeptides and glutamate, which are responsible of nociception. Therefore, there is increasing evidence that the therapeutic effect in both motor and autonomic disorders is based on a complex mode of botulinum neurotoxin action modulating the activity of efferent as well as afferent nerve fibres.

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“…The length of BoNT-induced intoxication may depend on (1) how long the cleaved SNARE proteins remain in the cytosol and the ability of the cleaved SNARE proteins to maintain the block to exocytosis, (2) how long the BoNT protease remains in place to cleave newly synthesised SNARE proteins, (3) the rate at which the neuron is able to replenish uncleaved SNARE proteins relative to ongoing cleavage, and (4) the ability of the presynaptic terminal to remodel in order to overcome the temporary paralysis. There is preclinical evidence for all these hypotheses [67]. The ubiquitination pathway has been proposed as a main mechanism responsible for degradation of the LC in the cytosol, thus terminating BoNT activity [68].…”

Section: Protease Domainmentioning

confidence: 99%

Botulinum Neurotoxin: A Multifunctional Protein for the Development of New Therapeutics

Fonfría¹

2018

Neurotoxins

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Botulinum neurotoxin (BoNT) is a major therapeutic agent licensed in neurological indications such as dystonia and spasticity. In recent years, its use has steadily increased in other neurological areas and new therapeutic areas and also in the aesthetic setting. Paradoxically, BoNT is also the causative agent of the disease botulism and a potential bioterrorism toxin. The BoNT family of toxins comprised more than 40 individual members, classified into 7 serotypes and are produced by Gram-positive obligate anaerobic bacteria. BoNTs are enzymatic multi-modular proteins with a complex multistep mechanism of action. Their target site is at peripheral neurons, particularly the neuromuscular junction, at which they inhibit acetylcholine neurotransmission. Despite intense activity in the BoNT field, today there are still gaps in knowledge both in clinical practice and in basic research. The discovery of the structure-function of BoNT and its domains has allowed rational design of new features using molecular engineering. The diversity of BoNT molecules, both natural and engineered, is an invaluable pool from which to design future new therapeutics with unique pharmacological properties for current and novel indications.

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Persistence of Botulinum Neurotoxin Inactivation of Nerve Function

Cited by 26 publications

References 58 publications

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

The binding of botulinum neurotoxins to different peripheral neurons

Botulinum Neurotoxin: A Multifunctional Protein for the Development of New Therapeutics

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