Toxins 2011, 3(3), 207-217; doi:10.3390/toxins3030207
Article

Post-Intoxication Inhibition of Botulinum Neurotoxin Serotype A within Neurons by Small-Molecule, Non-Peptidic Inhibitors

1,* email, 2email, 1email, 1email, 1email, 1email, 1email, 1email and 1,* email
Received: 8 February 2011; in revised form: 10 March 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
(This article belongs to the Special Issue Development of Botulinum Toxin Drugs)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Botulinum neurotoxins (BoNTs) comprise seven distinct serotypes that inhibit the release of neurotransmitter across neuromuscular junctions, resulting in potentially fatal flaccid paralysis. BoNT serotype A (BoNT/A), which targets synaptosomal-associated protein of 25kDa (SNAP-25), is particularly long-lived within neurons and requires a longer time for recovery of neuromuscular function. There are currently no treatments available to counteract BoNT/A after it has entered the neuronal cytosol. In this study, we examined the ability of small molecule non-peptidic inhibitors (SMNPIs) to prevent SNAP-25 cleavage post-intoxication of neurons. The progressive cleavage of SNAP-25 observed over 5 h following 1 h BoNT/A intoxication was prevented by addition of SMNPIs. In contrast, anti-BoNT/A neutralizing antibodies that strongly inhibited SNAP-25 cleavage when added during intoxication were completely ineffective when added post-intoxication. Although Bafilomycin A1, which blocks entry of BoNT/A into the cytosol by preventing endosomal acidification, inhibited SNAP-25 cleavage post-intoxication, the degree of inhibition was significantly reduced versus addition both during and after intoxication. Post-intoxication application of SMNPIs, on the other hand, was nearly as effective as application both during and after intoxication. Taken together, the results indicate that competitive SMNPIs of BoNT/A light chain can be effective within neurons post-intoxication.
Keywords: botulinum neurotoxin; small molecule non-peptidic inhibitor; neutralizing antibody; Bafilomycin A1
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MDPI and ACS Style

Ruthel, G.; Burnett, J.C.; Nuss, J.E.; Wanner, L.M.; Tressler, L.E.; Torres-Melendez, E.; Sandwick, S.J.; Retterer, C.J.; Bavari, S. Post-Intoxication Inhibition of Botulinum Neurotoxin Serotype A within Neurons by Small-Molecule, Non-Peptidic Inhibitors. Toxins 2011, 3, 207-217.

AMA Style

Ruthel G, Burnett JC, Nuss JE, Wanner LM, Tressler LE, Torres-Melendez E, Sandwick SJ, Retterer CJ, Bavari S. Post-Intoxication Inhibition of Botulinum Neurotoxin Serotype A within Neurons by Small-Molecule, Non-Peptidic Inhibitors. Toxins. 2011; 3(3):207-217.

Chicago/Turabian Style

Ruthel, Gordon; Burnett, James C.; Nuss, Jonathan E.; Wanner, Laura M.; Tressler, Lyal E.; Torres-Melendez, Edna; Sandwick, Sarah J.; Retterer, Cary J.; Bavari, Sina. 2011. "Post-Intoxication Inhibition of Botulinum Neurotoxin Serotype A within Neurons by Small-Molecule, Non-Peptidic Inhibitors." Toxins 3, no. 3: 207-217.

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