Glycopeptide synthesis and the effects of glycosylation on protein structure and activity.

Abstract

Despite the omnipresence of protein glycosylation in nature, little is known about how the attachment of carbohydrates affects peptide and protein activity. One reason is the lack of a straightforward method to access biologically relevant glycopeptides and glycoproteins. The isolation of homogeneous glycopeptides from natural sources is complicated by the heterogeneity of naturally occuring glycoproteins. It is chemical and chemoenzymatic synthesis that is meeting the challenge to solve this availability problem, thus playing a key role for the advancement of glycobiology. The current art of glycopeptide synthesis, albeit far from being routine, has reached a level of maturity that allows for the access to homogeneous and pure material for biological and medicinal research. Even the ambitious goal of the total synthesis of an entire glycoprotein is within reach. It is demonstrated that with the help of synthetic glycopeptides the effects of glycosylation on protein structure and function can be studied in molecular detail. For example, in immunology, synthetic (tumour-specific) glycopeptides can be used as immunogens to elicit a tumour-cell-specific immune response. Again, synthetic glycopeptides are an invaluable tool to determine the fine specificity of the immune response that can be mediated by both carbohydrate-specific B and T cells. Furthermore, selected examples for the use of synthetic glycopeptides as ligands of carbohydrate-binding proteins and as enzyme substrates or inhibitors are presented.