Glycopeptide Preparation and Application for Alzheimer?s Diagnostics and Influenza Immunization
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Date of Award
Doctor of Philosophy (PhD)
Glycoproteins and glycopeptides are ubiquitous in nature but present challenges in clinical application. From a synthetic standpoint, they combine the difficulties of glycochemistry, namely regio- and stereo-specificity limitations, with the challenges inherent in peptide production. Yet their biological significance makes them impossible to ignore.
The pathology of Alzheimer’s Disease (AD) is characterized by the extracellular deposition of amyloid β peptides (Aβ) and intracellular accumulation of hyperphosphorylated tau protein (p-tau). The hyperphosphorylation of tau is known to occur in concert with the reduction of O-GlcNAc loading. Indeed, it is known that artificially forcing an increase in O-GlcNAc results in reduced phosphorylation, and vice versa, at several sites known to be highly phosphorylated in p-tau of AD patients. While the study of p-tau is advanced with many commercial antibodies available to researchers, glycosylated tau is less well studied. Here, an array of peptides representing a relevant subset of tau is prepared. The peptides are either unmodified or bear O-GlcNAc or phosphate modifications in all possible combinations. P-tau related antibodies currently used for the diagnosis of AD are then analyzed against the microarray to reveal their binding specificities with tau peptides in different forms of modifications. The microarray-based screen enables us to establish the true epitope of clinically relevant anti-tau antibodies to guide their use in the diagnosis of AD.
In another project, a CRM197-glycopeptide conjugate was prepared for the development of an anti-influenza vaccine. The glycopeptide borne by this conjugate contained three copies of a highly conserved region of the Influenza A hemagglutinin viral glycoprotein. This glycopeptide was linked to carrier protein CRM197 via a linker at a loading level of approximately 5-6 glycopeptides per protein. This conjugate was then evaluated as a potential vaccine candidate against a strain of Influenza A.
Gibbons, Christopher, "Glycopeptide Preparation and Application for Alzheimer?s Diagnostics and Influenza Immunization." Dissertation, Georgia State University, 2021.
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