Year of Award

2023

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Chemistry (Organic Option)

Department or School/College

Department of Chemistry and Biochemistry

Committee Chair

Dr. Orion Berryman

Commitee Members

Dr. Kendal Ryter, Dr. Orion Berryman, Dr. Nigel Priestley, Dr. Dong Wang, Dr. Philippe Diaz

Keywords

β-glucan, Dectin-1, glycodendrimer, glucan particles, triple helix, Mycobacterium tuberculosis

Subject Categories

Medicinal-Pharmaceutical Chemistry | Organic Chemistry

Abstract

Tuberculosis (TB) – an infectious disease caused by Mycobacterium tuberculosis (Mtb) – remains an epidemic worldwide contributing to millions of deaths each year. Vaccination is possibly the best means of addressing this global threat. In recent years, synergistic Th1 and Th17 immune responses have emerged as the key players for a vaccine-induced protection against TB. There is currently no vaccine approved for humans that elicits a Th17-mediated immune response. C-Type Lectin Receptors (CLR), specifically Dectin-1, a pattern recognition receptor (PRR) of β-1,3-glucans (β-glucans) primarily from fungi cell walls, is known to induce a Th17-mediated response. The Th17 response upon binding of β-glucan and activation of Dectin-1 is determined by the size of the β-glucan. However, the mechanism of activation is poorly understood. It is suggested that three individual β-glucan strands assemble to form a triple helix and mimic the particulate β-glucan. In this study, we designed a scaffold that displays three glucan/reducing sugar molecules, where the scaffold can help induce the triple helix formation. A model trivalent glucose was synthesized via a convergent synthetic approach based on this design. Modular synthesis of multivalent sugars starting from a common scaffold, however, is a more practical and efficient synthetic strategy than the convergent synthesis. The common scaffold was synthesized starting from aminotriester. After deprotecting the Boc groups of the common scaffold, we successfully glycosylated of the scaffold with three glucose molecules and synthesized the trivalent glucose. We also attempted to conjugate other reducing sugars (maltose, maltotriose, laminarihexaose) but were unsuccessful in confirming their conjugation via mass spectrometry because of their low ionization efficiency. The anomeric proton linked to the aminopyridine of trivalent glucose, trivalent maltose, trivalent maltotriose are slightly upfield shifted in 1H NMR; however, the anomeric proton of the trivalent laminarihexaose was not observed due to solvent peak obstruction. C13 NMR showed that the anomeric carbon linked to the aminopyridine is upfield shifted which follows the trend of upfield shifted anomeric proton. Although the activity of trivalent sugars was not be determined, this study established the design and synthesis of a differentially protected scaffold which will be an invaluable tool for the investigation of β-glucan binding and Dectin-1 activation.

Download

Share

COinS
 

© Copyright 2023 Jasper Alinea Aquino