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Glycans as drug targets

Glycans are the carbohydrate chains of glycoproteins, proteoglycans, and glycolipids. For many years, glycans were thought to play merely structural roles in cells, but research has shown that they participate in fundamental properties of cells including protein quality control, cell adhesion and motility, endocytosis, and signal transduction [1]. Glycans have also been shown to affect processes important in development, such as cell proliferation and differentiation, and morphogenesis.


Glycans play key active roles in a number of human diseases. For example, glycans have been implicated in tumor growth and metastasis in breast, colon, prostate, melanoma, and other forms of cancer [2-11] . Glycans have also been implicated in various forms of inflammatory disease including asthma and dermatitis [12, 13]. Glycans are also pathogenic in lysosomal storage diseases, a group of approximately forty inherited diseases characterized by defects in lysosomal function [14].


Past attempts at developing drugs that target glycans have been limited by slow and expensive carbohydrate chemistry as well as the lack of effective glycan-targeted high-throughput screening methods. Zacharon has created novel high-throughput screening methods to overcome these limitations and identify glycan-targeted small molecule drugs with strong efficacy and safety profiles.





  1. Brown, J.R., B.E. Crawford, and J.D. Esko, Glycan antagonists and inhibitors: a fount for drug discovery. Crit Rev Biochem Mol Biol, 2007. 42(6): p. 481-515.
  2. Valentino, L., et al., Shed tumor gangliosides and progression of human neuroblastoma. Blood, 1990. 75(7): p. 1564-7.
  3. Deng, W., R. Li, and S. Ladisch, Influence of cellular ganglioside depletion on tumor formation. J Natl Cancer Inst, 2000. 92(11): p. 912-7.
  4. Weiss, M., et al., Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase. Cancer Res, 2003. 63(13): p. 3654-8.
  5. Zeng, G., et al., Alteration of ganglioside composition by stable transfection with antisense vectors against GD3-synthase gene expression. Biochemistry, 1999. 38(27): p. 8762-9.
  6. Zeng, G., L. Gao, and R.K. Yu, Reduced cell migration, tumor growth and experimental metastasis of rat F-11 cells whose expression of GD3-synthase is suppressed. Int J Cancer, 2000. 88(1): p. 53-7.
  7. Fuster, M.M. and J.D. Esko, The Sweet and Sour of Cancer: Glycans as Novel Therapeutic Targets. Nature Reviews in Cancer, 2005. 5: p. 526-542.
  8. Fuster, M.M., et al., Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J Cell Biol, 2007. 177(3): p. 539-49.
  9. Nakagoe, T., et al., Expression of ABH/Lewis-related antigens as prognostic factors in patients with breast cancer. J Cancer Res Clin Oncol, 2002. 128(5): p. 257-64.
  10. Nakamori, S., et al., Involvement of carbohydrate antigen sialyl Lewis(x) in colorectal cancer metastasis. Dis Colon Rectum, 1997. 40(4): p. 420-31.
  11. Brown, J.R., et al., A disaccharide-based inhibitor of glycosylation attenuates metastatic tumor cell dissemination. Clin Cancer Res, 2006. 12(9): p. 2894-901.
  12. Beeh, K.M., Bimosiamose, an inhaled small-molecule pan-selectin antagonist, attenuates late asthmatic reactions following allergen challenge in mild asthmatics: a randomized, double-blind, placebo-controlled clinical cross-over trial. Pulm Pharmacol Ther, 2006. 19: p. 233-241.
  13. Ikegami-Kuzuhara, A., Therapeutic potential of a novel synthetic selectin blocker, OJ-R9188, in allergic dermatitis. Br J Pharmacol, 2001. 134: p. 1498-1504.
  14. Scriver, ed. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. 2001.
  15. Kim, Y.J., et al., P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci U S A, 1998. 95(16): p. 9325-30.
  16. Kim, Y.J., et al., Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium. Am J Pathol, 1999. 155(2): p. 461-72.
  17. Shirota, K., Anti-metastatic effect of the sialyl Lewis-X analog GSC-150 on the human colon carcinoma derived cell line KM12-HX in the mouse. Biol Pharm Bull, 2001. 24: p. 316-319.
  18. Ulbrich, H.K., A novel class of potent nonglycosidic and nonpeptidid pan-selectin inhibitors. J Med Chem, 2006. 49: p. 5988-5999.
  19. Granovsky, M., et al., Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med, 2000. 6(3): p. 306-12.

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