Presentation Title

Sulfonamide peptide hydroxamic acid inhibitors for the Botulinum Neurotoxin

Start Date

November 2016

End Date

November 2016

Location

HUB 302-160

Type of Presentation

Poster

Abstract

The Botulinum neurotoxin (BoNT) is secreted by the Clostridium botulinum bacteria. The neurotoxin is one of the most lethal toxins known to man due to its potency and its ease of extraction from the bacteria. BoNTs are composed of heavy (HC) and light (LC) chain proteins. Upon exposure to BoNT, the HC bind to nerve cells and inject the LCs into the cytosol of the cell. The LCs are a zinc metalloprotease responsible for the cleaving of SNARE proteins in the synaptic cleft between neurons and muscles. Terminating neurotransmissions results in muscle paralysis which can lead to death.

Our laboratory focuses on small molecule therapeutics to inhibit this protease to cure botulism. Previously, we discovered a biphenyl sulfonamide isoleucine hydroxamic acid inhibitor for the BoNT LC. We hypothesized that increasing the number of amino acids in the scaffold would improve binding to the protease. The amino acids that were utilized in the new library were alanine, glycine, isoleucine, leucine, phenylalanine and valine. The new inhibitors were created via a solid phase synthetic strategy with hydroxylamine Wang resin. Amino acids were coupled to the resin in varied sequences to vary the results, the sulfonyl chloride was added to give the sulfonyl-amide bond and the small molecule was cleaved from the resin with trifluoroacetic acid. Fluorescence Resonance Energy Transfer assay was utilized to evaluate the molecules as inhibitos. The sequences containing alanine-isoleucine, isoleucine-glycine, and isoleucine-valine displayed 89% or greater inhibition of the BoNT LC at a concentration of 10 µM.

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Sulfonamide peptide hydroxamic acid inhibitors for the Botulinum Neurotoxin

HUB 302-160

The Botulinum neurotoxin (BoNT) is secreted by the Clostridium botulinum bacteria. The neurotoxin is one of the most lethal toxins known to man due to its potency and its ease of extraction from the bacteria. BoNTs are composed of heavy (HC) and light (LC) chain proteins. Upon exposure to BoNT, the HC bind to nerve cells and inject the LCs into the cytosol of the cell. The LCs are a zinc metalloprotease responsible for the cleaving of SNARE proteins in the synaptic cleft between neurons and muscles. Terminating neurotransmissions results in muscle paralysis which can lead to death.

Our laboratory focuses on small molecule therapeutics to inhibit this protease to cure botulism. Previously, we discovered a biphenyl sulfonamide isoleucine hydroxamic acid inhibitor for the BoNT LC. We hypothesized that increasing the number of amino acids in the scaffold would improve binding to the protease. The amino acids that were utilized in the new library were alanine, glycine, isoleucine, leucine, phenylalanine and valine. The new inhibitors were created via a solid phase synthetic strategy with hydroxylamine Wang resin. Amino acids were coupled to the resin in varied sequences to vary the results, the sulfonyl chloride was added to give the sulfonyl-amide bond and the small molecule was cleaved from the resin with trifluoroacetic acid. Fluorescence Resonance Energy Transfer assay was utilized to evaluate the molecules as inhibitos. The sequences containing alanine-isoleucine, isoleucine-glycine, and isoleucine-valine displayed 89% or greater inhibition of the BoNT LC at a concentration of 10 µM.