Carbohydrates chains that are covalently linked to proteins or lipids displayed on the cell surface have recently been shown to mediate many important physiological phenomena such as cell-cell or cell-matrix communication and signal transduction. As a consequence, these glycans play critical roles in many biological processes, such as inflammation, coagulation, cell motility, cell-matrix remodeling, antigenic recognition and tumor metastasis. In fact, an established hallmark of tumorigenesis is the biosynthesis of aberrant glycan chains due to changes in the expression of glycoprocessing enzymes. These aberrations become more marked as the tumor acquires a more aggressive phenotype. Many of these glycans are known tumor-associated antigens, and have been used as haptens in the development of tumor vaccines. The role that chemistry plays in this research area is threefold: 1) Defining the manner in which carbohydrates bind to proteins, 2) Unraveling the preferences of glycoprocessing enzymes for different sugar conformations and 3) Developing new synthetic techniques for the rapid and efficient preparation of oligosaccharides as tools for cellular studies. We have developed a vastly improved synthesis of an amino acid building block containing the Thomsen-Friedenreich (Tf) antigen(Galb1-3GalNAc), a glycan found in aggressive tumor cells but rarely in normal tissue, for the incorporation into peptides. In addition, we have prepared self-assembled gold nanoparticles containing this antigen to study the biological consequences of a multivalent presentation of this disaccharide. We are now planning the synthesis of multivalent constructs of Tf-containing glycopeptides derived from colon and breast cancer mucin structures as potentially highly potent immunogens for antibody production targeted to the glycosylated peptide structures. It is reasoned that since an immune response is mounted to both peptide and sugar antigens, the correct combination of the two may raise the titer of the antibody response while also stimulating a T-cell based attack. We have previously collaborated with members of the NCI on antibody binding studies of glycopeptides derived from HIV-1 and plan to continue this cooperation with this study. We have also enlisted experts from the University of Missouri to screen the multivalent constructs for inhibition of tumor cell binding to Galectin-3, a carbohydrate binding protein that is highly expressed in tumor tissue.
| Sundgren, Andreas; Barchi Jr, Joseph J (2008) Varied presentation of the Thomsen-Friedenreich disaccharide tumor-associated carbohydrate antigen on gold nanoparticles. Carbohydr Res 343:1594-604 |
