Access Type

Open Access Dissertation

Date of Award

1-1-2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Zhongwu Guo

Abstract

This dissertation is divided into two chapters describing the background, significance, and synthesis of GPI anchors and GPI-anchored molecules. GPI anchors are a class of complex glycolipids with the primary purpose of attaching cell surface proteins/glycoproteins to the cell membrane. The first chapter is focused on the synthesis of functionalized GPI anchors, and begins with an introductory look at the discovery, structure, biosynthesis, and biological functions of GPIs. Then, after surveying progress and achievements in GPI synthesis, including discussion about current strategic shortcomings in the field that prevent the chemical synthesis of various GPI derivatives, our approach to accessing uniquely functionalized GPI anchors is described. By employing the para-methoxybenzyl group for global hydroxyl protection, rather than traditional benzyl- or acyl-based protection, several functionalized GPI anchors were synthesized, including GPIs bearing unsaturated lipid chains, an alkyne-containing `clickable' GPI anchor, and a biotinylated GPI anchor.

In the second chapter, the topic is shifted from the GPI itself to a GPI-anchored molecule, namely the human CD52 antigen, which is a 12-amino acid glycopeptide containing a single N-glycosylation site, to which complex glycans are attached. This glycoconjugate exists in two distinct functional forms, including lymphocyte and sperm CD52, which are involved in the human immune and reproductive systems, respectively. The contrasting biological functions arise from structural differences in their N-glycan and GPI anchor, raising the topic of how N-glycosylation and GPI-anchorage affect peptide structure, and consequently, activity. To probe this question, we synthesized several CD52 peptides and glycopeptides and compared their conformational profiles using circular dichroism. This work, as well as brief introductions to N-glycosylation, the CD52 antigen, and chemical synthesis of glycopeptides are discussed the second chapter.

Both chapters contain extensive experimental details for the preparation of all unknown compounds. Appendices A and B provide selected characterization data, including NMR, MS, and HPLC chromatograms, for chapters 1 and 2, respectively.

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