Synthesis and evaluation of glycomimetic inhibitors of infectious diseases

Byrne, Syl
Sialic acids are a family of 9-carbon α-keto acid monosaccharides. Sialic acids are critical factors in various biological events, which will be discussed over the course of this thesis. Chapter 1 provides a literature review on sialic acids, their occurrence in nature and interactions with proteins in biological systems, from the view of both the immune defence and pathogenicity. Finally, there is a summary of the rising interest of glycomimetic research as well as the highlighting of the importance of glycan conformation in the binding event. Chapter 2 details the synthesis of ligands for Influenza hemagglutinin. These include both known natural disaccharides as well as new glycomimetics of the natural sia(2-3)gal disaccharide which is have been conformationally constrained. The latter builds on work carried out previously in the host laboratory group. This chapter reports and improvement in the synthesis of FB127 as well as new analogues of FB127. In addition, efforts were undertaken to develop synthetic routes towards constrained disaccharides via modification of the C3 position of sialic acid. Unfortunately, over the course of this PhD these efforts were unsuccessful but lay the ground for future investigations. Chapter 3 involves the expression and purification of SSL11, a protein believed to be a key player in the progression of infection caused by Staphylococcus Aureus and related strains. Here, the potential of the constrained compounds introduced in Chapter 2 to bind to this target were explored. This led to the structural elucidation of the SSL11-FB127 complex by X-ray diffraction. In addition, the binding affinity of natural sialylated ligands was evaluated using isothermal titration calorimetry (ITC) providing an indication into the minimal binding epitope and give thermodynamic data for the interaction. Chapter 4 involves rational based ligand design stemming from the biophysical data obtained from Chapter 3. The crystal structure identified areas that could be accessed synthetically with the aim of increasing the enthalpic contribution to the binding. The ITC data indicated a that the natural disaccharide was a good starting point for inhibitor development with a Kd of 8.6 mM towards SSL11. This stimulated the synthesis of a small library of compounds as potential inhibitors of SSL11. The evaluation of these compounds is currently ongoing during the completion of this thesis. Finally, Chapter 5 outlines the synthetic procedures used in obtaining the compounds discussed in Chapters 2 and 4, as well as their characterisation as determined with the help of NMR and HRMS.
NUI Galway
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland