Date of Award

2020

Document Type

Thesis

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Carlos A Sanhueza Chavez

Second Advisor

Sabesan Yoganathan

Third Advisor

Nitesh Kunda

Abstract

αGal or Galili epitope (αGal(1→3)βGal(1→4)GlcNAc) is a natural trisaccharide associated with cell-surface glycoproteins of certain mammalian and non-mammalian cells. The saccharide is not expressed by humans and anti-αGal antibodies account for ~1% of the total circulating antibodies in sera as a result of our constant exposition to the antigen from food and intestinal flora. Our interest in αGal relies on its involvement in a variety of pathologies including red meat allergy, hyperacute xenotransplant rejection, and parasitic and bacterial infections. In particular, we have an interest in developing structurally simple glycomimetics for engaging in high-affinity binding αGal-recognizing receptors such as the human anti-αGal IgG antibody and the Clostridium difficile toxins TcdA and TcdB in order to develop αGal based vaccine adjuvants and novel anti-infective therapies respectively. This communication presents our progress towards the synthesis of fluorinated αGal analogues as glycomimetics for their further applications to these goals. Apart from the role of carbohydrates in immune response, energy storage and as structural building blocks they are also involved in various other biological activities and many processes including cell-cell communication, immune response, fertilization, protein recycling, infection, among many others. The success of protein-carbohydrate interactions is conditioned to the fulfillment of conformational requirements imposed by the recognition site in the protein over the, inherently flexible, carbohydrate ligand. Hence, the study of the conformational preferences of saccharides is fundamental for the understanding of protein-carbohydrate interactions. In the second half of this thesis, we describe the results of the conformational study of rutinose (αRha(1→6)βGlcOR) glycosides. In particular, we centered our study on how the nature of the aglycone substituent can modulate the conformational equilibria around the interglycosidic linkage. Given the inherent flexibility of the (1→6) linkage, the hydrophobic nature of the rhamnose moiety, and the simplicity of the NMR spectra, rutinose constitutes a convenient model saccharide for performing these studies. The spectroscopic evidence gathered suggest the existence of an effect that could be used in the rational design of conformational mimetics of bioactive carbohydrates.

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