Presentation Title

Botulinum Neurotoxin Light Chain A Inhibitors

Advisor Information

James Hagen

Location

Milo Bail Student Center Ballroom

Presentation Type

Poster

Start Date

8-3-2013 9:00 AM

End Date

8-3-2013 12:00 PM

Abstract

Botulinum neurotoxins (BoNTs) are microbial products from the spore forming bacteria, Clostridium botulinum, that naturally inhabits soil and untreated water worldwide. The BoNTs have been recognized as the most potent, lethal toxins known to humans. BoNTs act as zinc dependent proteases that cleave soluble n-ethylmaleimide-sensitive factor attachment protein receptor proteins that control the release of neuronal vesicles which release acetylcholine into the neuromuscular junction. This inhibition of acetylcholine release can lead to the potentially fatal disease, botulism. Advanced intoxication can lead to flaccid paralysis, respiratory failure, and cardiac arrest. The serotype most commonly associated with human botulism is BoNT/A. BoNTs are single polypeptide chains that are approximately 150 kilodaltons (kDa) each. BoNT/A is cleaved resulting in a 100 kDa heavy chain (HC) and a 50 kDa light chain (LC). In order to counteract the toxins, an inhibitor must have high binding affinity to the BoNT/A LC. The inhibitor must be able to either bind directly to the catalytic zinc of the BoNT/A LC, or block the toxins from accessing the catalytic zinc site. This research has fused together known inhibitor segments to produce mild zinc binding inhibitors. These synthesized inhibitors are to be analyzed for purity by combustion analysis and biological activity to be studied in order to assess whether they can act as vaccines or antibodies in post toxin exposure from potential bioterrorism aerosol attacks of BoNTs or in accidental medicinal overdoses that may occur from medicinal or cosmetic uses of BoNTs.

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Mar 8th, 9:00 AM Mar 8th, 12:00 PM

Botulinum Neurotoxin Light Chain A Inhibitors

Milo Bail Student Center Ballroom

Botulinum neurotoxins (BoNTs) are microbial products from the spore forming bacteria, Clostridium botulinum, that naturally inhabits soil and untreated water worldwide. The BoNTs have been recognized as the most potent, lethal toxins known to humans. BoNTs act as zinc dependent proteases that cleave soluble n-ethylmaleimide-sensitive factor attachment protein receptor proteins that control the release of neuronal vesicles which release acetylcholine into the neuromuscular junction. This inhibition of acetylcholine release can lead to the potentially fatal disease, botulism. Advanced intoxication can lead to flaccid paralysis, respiratory failure, and cardiac arrest. The serotype most commonly associated with human botulism is BoNT/A. BoNTs are single polypeptide chains that are approximately 150 kilodaltons (kDa) each. BoNT/A is cleaved resulting in a 100 kDa heavy chain (HC) and a 50 kDa light chain (LC). In order to counteract the toxins, an inhibitor must have high binding affinity to the BoNT/A LC. The inhibitor must be able to either bind directly to the catalytic zinc of the BoNT/A LC, or block the toxins from accessing the catalytic zinc site. This research has fused together known inhibitor segments to produce mild zinc binding inhibitors. These synthesized inhibitors are to be analyzed for purity by combustion analysis and biological activity to be studied in order to assess whether they can act as vaccines or antibodies in post toxin exposure from potential bioterrorism aerosol attacks of BoNTs or in accidental medicinal overdoses that may occur from medicinal or cosmetic uses of BoNTs.