Presentation Title

Structure activity relationship study of Peptidomimetic Inhibitors for the Botulism Neurotoxin Serotype A

Faculty Mentor

Nicholas T. Salzameda

Start Date

17-11-2018 12:30 PM

End Date

17-11-2018 2:30 PM

Location

CREVELING 4

Session

POSTER 2

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

The botulinum neurotoxin (BoNT) is the most toxic protein known to man causing the neuroparalytic disease, Botulism. The neurotoxin consists of a heavy (HC) and light chain (LC) that work together to cause Botulism in humans. Once humans are infected with the toxin, the HC attaches to nerve cells and injects the LC into the cytosol. The LC is a zinc metalloprotease that cleaves SNARE proteins required for neurotransmission. The BoNT potency and ease of production perpetuate BoNT as a possible bioterrorism weapon. A therapeutic avenue for treatment of botulism is inhibition of the BoNT LC by small molecule inhibitors.

The goal of our research is to design therapeutics to inhibit the BoNT LC. This was accomplished by synthesizing a novel scaffold that mimics peptide bonding to the active site. The scaffold contains an amino acid functionalized with a hydroxamic acid at the C-terminus and a biphenyl ring system connected by a sulfonamide at the N-terminus. A library of compounds was synthesized to probe the sulfonamide linker.

The compounds were evaluated for inhibition by an enzymatic assay. Based on the results the sulfonamide is a vital linker for inhibition. Replacement of this linker with an amine greatly reduced inhibition. It is hypothesized that the amine enhances flexibility of the molecule adapting an unfavorable binding conformation while the sulfonamide is an ideal mimic of an amide and provided compounds with good inhibition.

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Nov 17th, 12:30 PM Nov 17th, 2:30 PM

Structure activity relationship study of Peptidomimetic Inhibitors for the Botulism Neurotoxin Serotype A

CREVELING 4

The botulinum neurotoxin (BoNT) is the most toxic protein known to man causing the neuroparalytic disease, Botulism. The neurotoxin consists of a heavy (HC) and light chain (LC) that work together to cause Botulism in humans. Once humans are infected with the toxin, the HC attaches to nerve cells and injects the LC into the cytosol. The LC is a zinc metalloprotease that cleaves SNARE proteins required for neurotransmission. The BoNT potency and ease of production perpetuate BoNT as a possible bioterrorism weapon. A therapeutic avenue for treatment of botulism is inhibition of the BoNT LC by small molecule inhibitors.

The goal of our research is to design therapeutics to inhibit the BoNT LC. This was accomplished by synthesizing a novel scaffold that mimics peptide bonding to the active site. The scaffold contains an amino acid functionalized with a hydroxamic acid at the C-terminus and a biphenyl ring system connected by a sulfonamide at the N-terminus. A library of compounds was synthesized to probe the sulfonamide linker.

The compounds were evaluated for inhibition by an enzymatic assay. Based on the results the sulfonamide is a vital linker for inhibition. Replacement of this linker with an amine greatly reduced inhibition. It is hypothesized that the amine enhances flexibility of the molecule adapting an unfavorable binding conformation while the sulfonamide is an ideal mimic of an amide and provided compounds with good inhibition.