Doctor of Philosophy (PhD)
Research and design of drugs for treatment against microbial infections require the study of pathogenic proteins involved during infection and replication. Drugs can be designed to interfere with the interaction network of these pathogenic proteins and inhibit the infection process. Determination of the structure and ligands of the target proteins in microbes is essential for designing mechanistic-based drugs. Two Chlamydia proteins involved in host cell invasion were investigated in this study. The goal is to identify amino acids involved at the binding interface of Chlamydia chaperon proteins Scc1 and Scc4 by solution NMR spectroscopy. This information will give a lead in designing drugs that will interfere with Scc1:Scc4 binding, thus preventing Chlamydia invasion. Two new purification methods for isolating untagged Scc4 and the formation of mixed heterodimer complexes for NMR studies are described. The experimental NMR spectroscopy data was recorded and used to analyze the structural conformations of Scc4 when transitioning from homodimer to the heterodimer complex. Research presented in the second section is a novel structural modification method for therapeutic peptides through glycoalkylation. The modification is intended to improve the pharmacokinetic properties of lysine-containing peptide drugs, through half-life elongation and increased oral bioavailability. Specifically, the therapeutic tripeptide, Ac‑KPV-NH2, was modified with a sugar derivative. Although the effect of the modification could not be assessed through antimicrobial and anti-inflammatory tests, the glycoalkylated peptides are shown to be stable against pronase cleavage. The unmodified tripeptide was cleaved by pronase in less than 24 hours, indicating that the glycoalkylation confers proteolytic stability.
Songok, Abigael Chebichiy, "NMR Structural Investigation of Chlamydial Protein Complex and Lysine Glycomimetic for Drug Design" (2018). LSU Doctoral Dissertations. 4677.
Available for download on Saturday, July 06, 2019