Structure-guided design and synthesis of SARS-COV-2 3CL protease inhibitors
AdvisorGroutas, William C.
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Howard, Dennis. 2022. Structure-guided design and synthesis of SARS-COV-2 3CL protease inhibitors -- In Proceedings: 21st Annual Undergraduate Research and Creative Activity Forum. Wichita, KS: Wichita State University, p. 8
There is a need for a diversified portfolio of direct-acting antivirals that can be used in the treatment and management of SARS-CoV-2 infections to complement the use of vaccines and monoclonal antibodies. The research objectives of my project are the following: 1. Multi-step synthesis, purification, structural characterization of an unnatural amino acid (glutamine surrogate) that serves as the primary specificity residue recognized by the protease. The purification of all intermediates and final compound entails the use of flash chromatography, and the structure of these compounds will be established using high field NMR. 2. The glutamine surrogate will be subsequently used in the synthesis of an array of inhibitors of SARS-CoV-2 3CL protease. This will involve the coupling of the glutamine surrogate to Leucine and other natural/unnatural amino acids, as well as a design element, that collectively interact with the protease and facilitate the docking of the inhibitors to the active site. The final inhibitors incorporate an aldehyde or a masked aldehyde as part of their structure that reacts with the catalytic cysteine residue located at the active site of the enzyme. I anticipate synthesizing a series of inhibitors that will be made available to two research groups that we collaborate with. One group at KU will be determining high-resolution xray crystal structures of our inhibitors bound to the enzyme. The second group at K-state- Vet school will be screening the compounds and conducting in-vitro studies to determine the potency of the inhibitors (IC50 values). My project will involve an iterative process of synthesis, cocrystal structure determination, and in-vitro screening. At the end of my project, I anticipate generating one or more series of compounds that are effective inhibitors of the protease. These results will be disseminated by submitting manuscripts for publication in peer-reviewed journals (I will be listed as a co-author).
Presented to the 21st Undergraduate Research and Creative Activity Forum (URCAF) held at the Rhatigan Student Center, Wichita State University, April 15, 2022.