Development of cancer vaccines from fully synthetic mucin-based glycopeptide antigens. A vision on mucins from the bioorganic chemistry perspective - Carbohydrate Chemistry: Chemical and Biological Approaches - page 533

Development of cancer vaccines from
fully synthetic mucin-based glycopeptide
antigens. A vision on mucins from the
bioorganic chemistry perspective
Alberto Fern ´ ndez-Tejada a and Samuel J. Danishefsky* a,b
DOI: 10.1039/9781849739986-00533
This chapter summarizes powerful chemical strategies for the synthesis of mucin-type
glycopeptides with special emphasis on the cassette assembly approach applied in our
laboratory. The review will focus mainly on efforts by our research group towards the
preparation of fully synthetic mucin-based cancer vaccines of clinical value, while briefly
acknowledging other key actors in the field.
1 Introduction
Mucins constitute a large class of cell surface or secreted, heavily glyco-
sylated proteins that contain both N-linked, and especially, O-linked
oligosaccharides. The common structural feature to all mucins is the
tandem-repeat domain, which comprises highly similar sequences rich
in serine (Ser) and threonine (Thr) residues. 1 However, the specific se-
quence and number of tandem repeats is highly variable among different
mucins. These residues are often found in contiguous clusters of two to
five units and, in most cases, are O-glycosylated with glycans ranging in
number from 3 to 20 carbohydrate units. Despite the large variety of
mucin glycostructures, the modality wherein the first glycan residue, an
N-acetylgalactosamine (GalNAc) moiety, is linked to a serine (Ser) or
threonine (Thr) through an a-O-linkage-the so-called ''mucin-like''
glycosylation-is broadly conserved. Normally, mucins carry complex and
highly branched O-linked carbohydrates that shield the protein core, and
are crucial to their structure and function. Mucin-type oligosaccharides
are known to serve as important recognition elements, and are involved
in a large number of cell-cell interactions. 2 Along with serving as
receptor-binding ligands, O-linked glycans can have a profound influence
on the structure and stability of the protein to which they are attached.
The importance of the mucin-type glycosylation has attracted a great deal
of interest in the synthesis of well-defined glycoproteins for structural
and functional studies. 3 Interestingly, the significant changes of the a-O-
glycosylation pattern in mucins during the malignant transformation
of normal epithelial cells to tumor cells generally results in shorter
carbohydrate chains arranged in clusters of two to five adjacent domains