Synthesis of novel chemical adjuvants for the modulation and study of CD1-d mediated immunological processes

Quaid, Padraic (2017). Synthesis of novel chemical adjuvants for the modulation and study of CD1-d mediated immunological processes. University of Birmingham. Ph.D.

[img] Quaid17PhD.pdf
PDF - Accepted Version
Restricted to Repository staff only until 22 May 2020.

Download (8MB) | Request a copy

Abstract

Presentation of antigens via cell-surface glycoproteins, such as MHC-I and CD1d, elicits an immune response. Antigen loading occurs in the endoplasmic reticulum with the help of chaperone proteins such as calreticulin. It has been shown that a Glc\(_1\)Man\(_3\) tetrasaccharide can be recognised. A biotinylated Glc\(_1\)Man\(_3\) was designed to bind to both calreticulin and streptavidin to allow isolation of the calreticulin–tetrasaccharide complex through pull-down experiments. The stereoselective synthesis of this biotinylated oligosaccharide is described. -galactosyl ceramide is the prototypical ligand of CD1d, its activation of iNKT cells produces a mixture of T\(_H\)1 and T\(_H\)2 cytokines, which limits its therapeutic application. Analogues that induce a biased cytokine response are therefore desirable. Analysis of the crystal structure of the CD1d–-GalCer–TCR complex reveals that the 6-OH and ring oxygen are not involved in binding. Analogues where these parts of the molecule have been excised, have led to the introduction of ThrCer and its cyclitol analogue ThrCer-6. We report a new and improved synthesis of ThrCer-6 and a series of analogues that were designed to elicit biased cytokine responses. Studies towards the preparation of ThrCer analogues involving modifications to the pseudo-glycosidic linkage are also described. Finally, the synthesis of ceramide analogues with the potential for conjugation through a photoreactive group to the CD1d protein are discussed.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Cox, LiamUNSPECIFIEDUNSPECIFIED
Fossey , J.S.UNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Engineering & Physical Sciences
School or Department: School of Chemistry
Funders: None/not applicable
Subjects: Q Science > QD Chemistry
URI: http://etheses.bham.ac.uk/id/eprint/7861

Actions

Request a Correction Request a Correction
View Item View Item

Downloads

Downloads per month over past year