Tumour-associated glycopeptide antigens and their modification in anticancer vaccines - Carbohydrate Chemistry: Chemical and Biological Approaches - page 507

Scheme 1 Typical tumour-associated O-glycans found on mucins.
numerous tandem repeats of the sequence GSTAPPAHGVTSAPDTRPAP
which includes the major O-glycosylation sites. 9 Due to changes in the
activity of glycosyltransferases in epithelial tumour cells, the carbohydrate
side chains of tumour-associated MUC1 are characteristically shorter and
often prematurely sialylated, compared to those of MUC1 on normal
cells. 2,10,11 As is generally found for glycoproteins, mucins are micro-
heterogenic with respect to their glycans. Thus, short, tumour-associated
carbohydrate antigens and complete oligosaccharide side chains are found
in various combinations on tumour-associated mucins. Tumour-associ-
ated MUC1 isolated from epithelial tumour cells is therefore not applicable
for the development of a suciently tumour-selective vaccine.
Chemical synthesis provides an array of powerful methods 12 to access
the conjugates 1-5 of the five major tumour-associated carbohydrates
linked to serine and threonine (Scheme 1).
These typical tumour-associated mucin O-glycan structures have
also been constructed using enzymatic methods. 13-16 However, the
presentation of different glycans within the glycopeptide antigen and a
regioselective coupling of the saccharides within the peptide chain are
dicult to achieve in such enzymatic syntheses. The chemical syntheses,
on the other hand, require selectively protected building blocks of
glycosyl amino acids of types 1-5, yet offer the advantage that these
building blocks can be introduced at any position within the tandem
repeat sequence of MUC1, for example. 12,17,18 Furthermore, these
building blocks can be modified, for example in order to enhance the
biological half-life of the synthetic glycopeptide vaccines. We therefore
focus in this survey on the chemical synthesis of the glycopeptide anti-
gens by stepwise peptide chain extension on solid-phase.
2 Synthesis of glycosyl amino acid building blocks
Conjugates of the tumour-associated carbohydrate antigens with
amino acids are required as the key compounds for the chemical
construction of tumour-associated glycopeptide antigens. First, the syn-
theses of O-glycosyl amino acids which contain the natural a-glycoside
linkage between N-acetyl-galactosamine and serine or threonine are
summarized, followed by the synthesis of some non-natural analogs.