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

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

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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.

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