Persistence of Botulinum Neurotoxin Inactivation of Nerve Function

Shoemaker, Charles B.; Oyler, George A.

doi:10.1007/978-3-662-45790-0_9

Cited by 3 publications

(4 citation statements)

References 58 publications

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“…LCA stands out for its cellular longevity, leading to persistent toxicity due to ongoing proteolysis of newly synthesized SNAP25. Different mechanisms had been proposed to account for persistence of BoNT/A intoxication (10,11). We have previously provided a molecular mechanism for the differential persistence of LCA compared with LCE by demonstrating that LCE is recognized by the ubiquitin ligase TRAF2 and rapidly degraded by the UPS (12).…”

Section: Discussionmentioning

confidence: 99%

“…One salient feature of BoNT intoxication, particularly by serotype A (BoNT/A), which blocks neurotransmission by cleaving SNAP25, is the persistence or long duration of paralysis, lasting 2-6 mo from a single exposure to the toxin (9,10). Although desirable for therapeutic applications, this extreme persistence presents special challenges for the clinical management of intoxication.…”

mentioning

confidence: 99%

“…The mechanisms for the differential persistence of BoNTs are not fully understood. Several factors may contribute to BoNT persistence, but the relative lifetime of BoNT LC proteases in the presynaptic terminal appears to play a predominant role (7,10,11). Cells normally degrade foreign proteins such as bacterial or viral proteins through the ubiquitin-proteasome system (UPS).…”

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confidence: 99%

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Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Tsai

Kotiya

Kiris

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Significance Botulinum neurotoxins (BoNTs) are the most potent biological toxins. These proteases function by cleaving SNARE proteins, leading to paralysis and death from respiratory failure. BoNT serotype A (BoNT/A) has the most prolonged symptoms due to an extraordinarily stable catalytic light chain (LCA). BoNT/A intoxication can occur through ingestion (either sporadically or from a common food source), as a consequence of a clinical mishap, or potentially through bioterrorism, which would require mass mechanical ventilation. We report that LCA persistence is due to a particular deubiquitinating enzyme that binds a specific region of LCA and prevents its ubiquitin-dependent proteasomal degradation. These findings represent an essential step toward developing targeted molecular approaches to reducing morbidity and mortality from this toxin.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Tsai

Kotiya

Kiris

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…First, therapeutics must be cell-permeant to be effective later in the course of intoxication when BoNTs are intracellular. Second, BoNTs are known to be highly persistent in neurons (BoNT/A can persist for 4–6 months in human neurons , ), so effective therapies must achieve sustained inactivation of the toxin. This persistence highlights the limitation of reversible inhibitors that are potent in vitro but that cannot achieve sustained inhibition in clinically relevant models.…”

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confidence: 99%

Covalent Modifiers of Botulinum Neurotoxin Counteract Toxin Persistence

et al. 2018

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Botulinum neurotoxins (BoNTs) are the most potent toxin known to man and a significant threat as a weapon of bioterrorism. BoNTs contain a metalloprotease domain that blocks neurotransmitter release in nerve terminals, resulting in a descending, flaccid paralysis with a 5-10% mortality rate. Existing treatment options cannot access or neutralize toxin following its endocytosis, so there is a clear need to develop novel therapies. Numerous substrate-based and zinc-chelating small-molecule inhibitors have been reported, however none have progressed to the clinic. This is likely due to the difficulty of reversible inhibitors to achieve sustained inhibition of the toxin, which has a months-long half-life in vivo. An alternative strategy to mitigate BoNT persistence is through covalent, irreversible inhibition of toxin function. However, few examples of covalent BoNT inhibitors have been reported. Here, we describe a competition-based screen to identify covalent modifiers of the conserved active-site adjacent cysteine C165 in the BoNT/A serotype. We found that compounds containing cysteine-reactive electrophiles designed to target cysteine proteases failed to bind C165 while selenide compounds were efficient covalent binders of this cysteine. Importantly, covalent modification at C165 resulted in sustained, irreversible inhibition of BoNT/A protease activity. Covalent selenide inhibitors were non-toxic and protective in a neuronal assay of intoxication making them promising new scaffolds for the study of the BoNT/A toxin as well as for the design of novel therapy agents.

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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 3 publications

References 58 publications

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Covalent Modifiers of Botulinum Neurotoxin Counteract Toxin Persistence

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

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