Synthesis of cyclic glycopeptide inhibitors of P-selectin and glycans from Gram negative bacteria

Abstract

Proteins are the most abundant and diverse class of biological macromolecules and are involved in virtually all physiological processes. The majority of proteins contain post-translational modifications (PTMs) which increase the number of unique biomolecules that can be generated from the genome of an organism by several orders of magnitude. Among these PTMs, the most structurally diverse modification is glycosylation, i.e. the addition of carbohydrate molecules to amino acid residues. Protein glycosylation, and glycans in general, serve a myriad of functions. For example, glycans presented on proteins can act as ligands for carbohydrate binding receptors such as P-selectin, and bacterial glycans are important virulence factors and essential for motility and host colonization. The overall topic of this thesis is the synthesis of novel cyclic glycopeptides that aim to target P-selectin and of the bacterial carbohydrate pseudaminic acid.

Chapter 1 gives a broad introduction to post-translational modifications, chemical peptide synthesis and macrocyclic peptides as a novel therapeutic modality. Chapter 2 describes the synthesis of cyclic glycopeptide inhibitors of P-selectin that were discovered using mRNA display technology with genetic code reprogramming of the non-canonical amino acids fucosyl-serine and sulfotyrosine. Their binding affinities for P-selectin were analysed via surface plasmon resonance. Chapter 3 describes the attempted total synthesis of pseudaminic acid, a carbohydrate that is unique to bacteria and is involved in the virulence of several critical Gram-negative bacteria, particularly species associated with antimicrobial resistance.