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Structure-guided design and synthesis of SARS-COV-2 3CL protease inhibitors
Howard, Dennis
Howard, Dennis
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2022-04-15
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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
Abstract
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).
Table of Contents
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Presented to the 21st Undergraduate Research and Creative Activity Forum (URCAF) held at the Rhatigan Student Center, Wichita State University, April 15, 2022.
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Wichita State University
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URCAF
v.21
v.21