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Post-Intoxication Inhibition of Botulinum Neurotoxin Serotype A within Neurons by Small-Molecule, Non-Peptidic Inhibitors
U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA
SAIC-Frederick, Inc., National Cancer Institute at Frederick, Target Structure-Based Drug Discovery Group, P.O. Box B, Frederick, MD 21702, USA
* Authors to whom correspondence should be addressed.
Received: 8 February 2011; in revised form: 10 March 2011 / Accepted: 11 March 2011 / Published: 15 March 2011
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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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.
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.
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.