Presentation Title

Investigating peptidomimetic scaffolds for inhibition of botulinum neurotoxin light chain

Faculty Mentor

Nicholas T. Salzameda

Start Date

18-11-2017 10:00 AM

End Date

18-11-2017 11:00 AM

Location

BSC-Ursa Minor 124

Session

Poster 1

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

Elizabeth Morales, Alejandra Yaneli Palomino, Dr. Nicholas T. Salzameda

Investigating peptidomimetic scaffolds for inhibition of botulinum neurotoxin light chain

The botulinum neurotoxin (BoNT), a lethal protein produced by the bacteria Clostridium botulinum causes botulism. The BoNT is categorized as a bioterrorist agent due to its ease of production and high toxicity that could be dispersed to large populations. The neurotoxin consists of a heavy (HC) and light chain (LC) that work together to cause muscle paralysis, which can lead to death. An attractive therapeutic avenue for the treatment of botulism are small molecules that can disrupt the enzymatic activity of the LC. This would provide an excellent therapeutic counteragent for mass distribution in the event of BoNT being used as a bioterrorist agent.

We have identified a molecular scaffold for inhibition of the BoNT/LC. The scaffold is centered around amino acids functionalized with a hydroxamic acid on the C-terminus and coupled to an aromatic ring via a sulfonyl amide bond on the N-terminus. We expanded our scaffold to include both amide and sulfonamide linkers on the N-terminus and varied the amino acid side chain.

The molecules were evaluated for inhibition of the BoNT/LC via a FRET enzymatic assay. Based on the assay results compounds with the sulfonamide linker showed better inhibition with D-amino acid stereoisomers while the amide linker prefers the L-amino acid. When the tert-butyl side chain was incorporated into the scaffold the sulfonyl amide linker had no inhibition while the amide linker resulted in 75% inhibition. We also expanded our scaffold by adding an additional amino acid but the inhibition was poor with the sulfonyl amide linker.

Botulinum Neurotoxin, Small molecule inhibitors, Amino Acid, Amide, Sulfonyl Amide, FRET Assay

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Nov 18th, 10:00 AM Nov 18th, 11:00 AM

Investigating peptidomimetic scaffolds for inhibition of botulinum neurotoxin light chain

BSC-Ursa Minor 124

Elizabeth Morales, Alejandra Yaneli Palomino, Dr. Nicholas T. Salzameda

Investigating peptidomimetic scaffolds for inhibition of botulinum neurotoxin light chain

The botulinum neurotoxin (BoNT), a lethal protein produced by the bacteria Clostridium botulinum causes botulism. The BoNT is categorized as a bioterrorist agent due to its ease of production and high toxicity that could be dispersed to large populations. The neurotoxin consists of a heavy (HC) and light chain (LC) that work together to cause muscle paralysis, which can lead to death. An attractive therapeutic avenue for the treatment of botulism are small molecules that can disrupt the enzymatic activity of the LC. This would provide an excellent therapeutic counteragent for mass distribution in the event of BoNT being used as a bioterrorist agent.

We have identified a molecular scaffold for inhibition of the BoNT/LC. The scaffold is centered around amino acids functionalized with a hydroxamic acid on the C-terminus and coupled to an aromatic ring via a sulfonyl amide bond on the N-terminus. We expanded our scaffold to include both amide and sulfonamide linkers on the N-terminus and varied the amino acid side chain.

The molecules were evaluated for inhibition of the BoNT/LC via a FRET enzymatic assay. Based on the assay results compounds with the sulfonamide linker showed better inhibition with D-amino acid stereoisomers while the amide linker prefers the L-amino acid. When the tert-butyl side chain was incorporated into the scaffold the sulfonyl amide linker had no inhibition while the amide linker resulted in 75% inhibition. We also expanded our scaffold by adding an additional amino acid but the inhibition was poor with the sulfonyl amide linker.

Botulinum Neurotoxin, Small molecule inhibitors, Amino Acid, Amide, Sulfonyl Amide, FRET Assay