Convergent total synthesis of a tumour-associated mucin motif

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Abstract

Synthetic glycoconjugates that mimic cell-surface tumour antigens (glycolipids or glycoproteins with unusual carbohydrate structural motifs) have been shown to trigger humoral responses in murine and human immune systems1,2,3. This raises the exciting possibility of inducing active immunity with fully synthetic carbohydrate vaccines, particularly if vaccine compounds can be synthesized that resemble the surface environment of transformed cells even more closely. Glycopeptides seem particularly suitable for this purpose. In contrast to most glycolipids and thecarbohydrates themselves, glycopeptides bind to major histocompatibility complex molecules, and, in favourable cases, can stimulate T cells and lead to the expression of receptors that recognize the carbohydrate part of a glycopeptide with high specificity4,5,6,7,8. The preparation of glycopeptides and glycoproteins remains, however, a difficult challenge9,10,11,12: earlier synthesis methods have been inefficient, and established cloning approaches that allow engineering of global glycopatterns produce only heterogeneous glycoproteins13. Here we report an efficient strategy of the synthesis of tumour-associated mucin glycopeptides with clustered trisaccharide glycodomains corresponding to the (2,6)-sialyl T antigen. Our approach involves construction of the complete glycodomain in the first stage, followed by convergent coupling to amino acid residues and subsequent incorporation of the glycosyl amino acid units into a peptide chain. This general strategy allows the assembly of molecules in which selected glycoforms can be incorporated at any desired position of the peptide chain. The resultant fully synthetic O-linked glycopeptide clusters are the closest homogeneous mimics of cell-surface mucins at present available, and so are promising compounds for the development of anticancer vaccines.

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Figure 1: Illustration of α-O-linked glycopeptides and the synthetic strategy reported here.
Figure 2: Assembly of trisaccharide glycal and donors.
Figure 3: Glycopeptide assembly and deblocking of protecting groups.
Figure 4: Fragment assembly of glycoprotein 20.

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Correspondence to Samuel J. Danishefsky.

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