CONVERGENT TOTAL SYNTHESIS OF A TUMOR-ASSOCIATED MUCIN MOTIF

Synthetic glycoconjugates that mimic cell-surface tumour antigens (gly colipids or glycoproteins with unusual carbohydrate structural motifs) have been shown to trigger humoral responses in murine and human immu ne systems(1-3). This raises the exciting possibility of inducing acti ve immunity with fully synthetic carbohydrate vaccines, particularly i f vaccine compounds can be synthesized that resemble the surface envir onment of transformed cells even more closely. Glycopeptides seem part icularly suitable for this purpose. In contrast to most glycolipids an d the carbohydrates themselves, glycopeptides bind to major histocompa tibility complex molecules, and, in favourable cases, can stimulate T cells and lead to the expression of receptors that recognize the carbo hydrate part of a glycopeptide with high specificity(4-8). The prepara tion of glycopeptides and glycoproteins remains, however, a difficult challenge(9-12): earlier synthesis methods have been inefficient, and established cloning approaches that allow engineering of global glycop atterns produce only heterogeneous glycoproteins(13). Here we report a n efficient strategy of the synthesis of tumour-associated mucin glyco peptides with clustered trisaccharide glycodomains corresponding to th e (2,6)-sialyl T antigen. Our approach involves construction of the co mplete glycodomain in the first stage, followed by convergent coupling to amino acid residues and subsequent incorporation of the glycosyl a mino acid units into a peptide chain. This general strategy allows the assembly of molecules in which selected glycoforms can be incorporate d at any desired position of the peptide chain. The resultant fully sy nthetic O-linked glycopeptide clusters are the closest homogeneous mim ics of cell-surface mucins at present available, and so are promising compounds for the development of anticancer vaccines.