Presentation Title

Structure activity relationship study of isoleucine sulfonamide hydroxamic acid inhibitors for the Botulinum Neurotoxin

Start Date

November 2016

End Date

November 2016

Location

HUB 302-150

Type of Presentation

Poster

Abstract

Botulism, a severe paralytic disease caused by the botulinum neurotoxin (BoNT), is produced via Clostridium botulinum bacterium. The BoNT is composed of heavy (HC) and light (LC) chains. The LC, a zinc metalloprotease, is inserted into the cytosol by the HC and cleaves SNARE proteins. BoNT is the most poisonous toxin known to man, due to the ease of obtaining it, there are concerns BoNT could be used for bioterrorism. Due to the lack of wide scale viable treatment options, our laboratory works on inhibiting the BoNT LC as a treatment option.

Previously, we designed small molecule inhibitors for the BoNT LC. These molecules contained a biphenyl ring attached to the N-terminus of isoleucine via a sulfonamide bond with a hydroxamic acid on th C-terminus. We continue improving the inhibitor by focusing on the biphenyl, the sulfonamide, and the number and position of chlorines on the biphenyl. These compounds were synthesized through a 4 step synthetic.

Based on an enzymatic inhibition assay, inhibitors that contained a chlorine at the meta position of the biphenyl displayed better inhibition than other analogs. When comparing the inhibition of compounds containing the sulfonamide or amide linker, it was determined that the amide linker displayed better inhibition. The best inhibitor containing the sulfonamide linker displayed an IC50 value of 20 µM. Based on the results we have a better understanding of small molecule structural requirements for BoNT/LC inhibition.

Keywords: Medicinal Chemistry, Neurotoxin, Botulism, Metalloprotease Inhibitor

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Structure activity relationship study of isoleucine sulfonamide hydroxamic acid inhibitors for the Botulinum Neurotoxin

HUB 302-150

Botulism, a severe paralytic disease caused by the botulinum neurotoxin (BoNT), is produced via Clostridium botulinum bacterium. The BoNT is composed of heavy (HC) and light (LC) chains. The LC, a zinc metalloprotease, is inserted into the cytosol by the HC and cleaves SNARE proteins. BoNT is the most poisonous toxin known to man, due to the ease of obtaining it, there are concerns BoNT could be used for bioterrorism. Due to the lack of wide scale viable treatment options, our laboratory works on inhibiting the BoNT LC as a treatment option.

Previously, we designed small molecule inhibitors for the BoNT LC. These molecules contained a biphenyl ring attached to the N-terminus of isoleucine via a sulfonamide bond with a hydroxamic acid on th C-terminus. We continue improving the inhibitor by focusing on the biphenyl, the sulfonamide, and the number and position of chlorines on the biphenyl. These compounds were synthesized through a 4 step synthetic.

Based on an enzymatic inhibition assay, inhibitors that contained a chlorine at the meta position of the biphenyl displayed better inhibition than other analogs. When comparing the inhibition of compounds containing the sulfonamide or amide linker, it was determined that the amide linker displayed better inhibition. The best inhibitor containing the sulfonamide linker displayed an IC50 value of 20 µM. Based on the results we have a better understanding of small molecule structural requirements for BoNT/LC inhibition.

Keywords: Medicinal Chemistry, Neurotoxin, Botulism, Metalloprotease Inhibitor