Anti-SpeB Small Molecule Inhibitor Library Can Be Synthesized Using a Fluorosulfonyl 2,3-Dimethyl Imidazol-3-Ium Triflate Salt in a SuFEx Reaction
Faculty Mentor Information
Dr. Sarah Hobdey (Mentor), Idaho Veterans Research and Education Foundation; and Dr. Don Warner (Mentor), Boise State University
Presentation Date
7-2024
Abstract
Infection by the group A streptococcus (GAS) bacteria Streptococcus pyogenes can result in a disease state called necrotizing fasciitis. This disease can progress rapidly, resulting in amputation or death. During infection, GAS produces a cysteine protease called Streptococcal Pyrogenic Exotoxin B (SpeB), which contributes to immune evasion by hydrolysis of host IgG. Lead modification of a small molecule inhibitor (SMI) for SpeB can create a therapeutic solution for GAS infection to allow for proper host immune response against GAS. Two analogs have been identified to have significant anti-SpeB activity, however the synthesis of these analogs is difficult due to a gaseous reagent that is both hard to obtain and dangerous to use. Alternative synthesis schemes using a safer and more available reagent creates a bioisostere (sulfonyl) of the product from the original synthesis scheme (imino fluoro sulfoxide). From this adduct, sulfur-fluoride exchange (SuFEx) click chemistry can be done to create a library of SMIs. A fluorometric biochemical assay measuring the hydrolytic activity of SpeB is utilized to screen for optimized leads on the criteria of efficacy and potency.
Anti-SpeB Small Molecule Inhibitor Library Can Be Synthesized Using a Fluorosulfonyl 2,3-Dimethyl Imidazol-3-Ium Triflate Salt in a SuFEx Reaction
Infection by the group A streptococcus (GAS) bacteria Streptococcus pyogenes can result in a disease state called necrotizing fasciitis. This disease can progress rapidly, resulting in amputation or death. During infection, GAS produces a cysteine protease called Streptococcal Pyrogenic Exotoxin B (SpeB), which contributes to immune evasion by hydrolysis of host IgG. Lead modification of a small molecule inhibitor (SMI) for SpeB can create a therapeutic solution for GAS infection to allow for proper host immune response against GAS. Two analogs have been identified to have significant anti-SpeB activity, however the synthesis of these analogs is difficult due to a gaseous reagent that is both hard to obtain and dangerous to use. Alternative synthesis schemes using a safer and more available reagent creates a bioisostere (sulfonyl) of the product from the original synthesis scheme (imino fluoro sulfoxide). From this adduct, sulfur-fluoride exchange (SuFEx) click chemistry can be done to create a library of SMIs. A fluorometric biochemical assay measuring the hydrolytic activity of SpeB is utilized to screen for optimized leads on the criteria of efficacy and potency.