Convergent total synthesis of a tumour-associated mucin motif Journal Article


Authors: Sames, D.; Chen, X. T.; Danishefsky, S. J.
Article Title: Convergent total synthesis of a tumour-associated mucin motif
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 systems. 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 the carbohydrates 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 specificity. The preparation of glycopeptides and glycoproteins remains, however, a difficult challenge: earlier synthesis methods have been inefficient, and established cloning approaches that allow engineering of global glycopatterns produce only heterogeneous glycoproteins. 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.
Keywords: unclassified drug; protein domain; protein assembly; tumor antigen; molecular sequence data; protein synthesis; murinae; carbohydrate sequence; mucin; mucins; trisaccharide; priority journal; article; (2,6) sialyl t antigen
Journal Title: Nature
Volume: 389
Issue: 6651
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 1997-10-09
Start Page: 587
End Page: 591
Language: English
DOI: 10.1038/39292
PUBMED: 9335496
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus
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MSK Authors
  1. Dalibor Sames
    9 Sames