Oligosaccharide Epitope Diversity and Therapeutic Potential

  • Elizabeth F. Hounsell
  • David V. Renouf
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 435)


In the search for new therapeutics based on oligosaccharide-protein interactions (glycotherapeutics) several unique features about glycans must be borne in mind; i.e., their structural diversity; the recognition of epitopes on branched sequences with local conformation; and, multivalent presentation. These characteristics are variously important in, for example, the potential exploitation of a) high affinity interactions of glycosaminoglycans (proteoglycan oligosaccharides) with proteins, b) monoclonal antibody, mammalian lectin and microorganism recognition of mucin-type oligosaccharides, and c) the functions of both lipid-linked oligosaccharides (glycolipids) and glycoproteins (GPI anchored). In the first, diverse sequence determinants (reviewed in Hounsell, 1994; Hounsell, 1995; Hounsell and Bailey, 1997) tend to be displayed at multiple sites along a linear polymer; in the second a high degree of peptide substitution and oligosaccharide branching leads to crowding of potential ligands (Hounsell et al., 1996); and, in the last, cooperativity may involve lipid-lipid, oligosaccharide-oligosaccharide and oligosaccharide-protein mediated clustering. These different strategies of nature can be explored by NMR spectroscopy of functional motifs modelled by computer graphics in the context of multi-component macromolecular systems (Hounsell, 1994; 1995).


Dermatan Sulphate Keratan Sulphate Glial Cell Derive Neurotrophic Factor Major Histocompatibility Complex Binding Lysosomal Acid Lipase 
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  1. Abel-Motal, U.M., Berg, L., Rosén, A., Bengtsson, M., Thorpe, C.J., Kihlberg, J., Dahmén, J., Magnusson, G., Karlsson, K-A., and Jondal, M., 1996, Immunization with glycosylated Kb-binding peptides generates carbohydrate-specific, unrestricted cytotoxic T cells. Eur. J. Immunol 26:544–551.CrossRefGoogle Scholar
  2. Barboni, E., Rivero, B.P., George, A.J.T., Martin, S.R., Renouf, D.V., Hounsell, E.F., Barber, P.C., Morris, R.J., 1995, The glycophosphatidylinositol anchor affects the conformation of the Thy-1 protein. J. Cell Sci. 108:487–497.PubMedGoogle Scholar
  3. Barclay, N.A., Birkeland, M.L., Brown, M.H., Beyers, A.D., Davis, S.J., Somoza, C., Williams, A.F. 1993, The Leucocyte Antigen Facts Book. Acad. Press Ltd, London.Google Scholar
  4. Campbell, J.B., Finnie, I.A., Hounsell, E.F., Rhodes, J.A., 1995. Direct demonstration of increased expression of Thomsen-Friedenreich (TF) antigen in colonic adenocarcinoma and ulcerative colitis mucin and its concealment in normal mucin. J. Clin Invest. 95:571–516.PubMedCrossRefGoogle Scholar
  5. Chai W., Hounsell E.F., Bauer C.J., Lawson AM. (1995) Characterisation by LSIMS and 1H-NMR of tetra-, hexa-and octasaccharides of porcine intestinal heparin. Carbohydrate Res. 269:139–156.CrossRefGoogle Scholar
  6. Chen, X., Rubock, M.J. and Whitman, M., 1996, A transcriptional partner for MAD proteins in TGF-β Signalling. Nature 383:691–696.PubMedCrossRefGoogle Scholar
  7. Collinge, J., Sidle, K.C.L., Meads, J., Ironside, J. and Hill, A.F., 1996. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CID. Nature 383:685–690.PubMedCrossRefGoogle Scholar
  8. Davies, M.J. and Hounsell, E.F. (1996a) Carbohydrate Chromatography: Towards Yoctomole Sensitivity. Biomed. Chrom. Vol.10 No.6 p285–289.CrossRefGoogle Scholar
  9. Davies, M. J. and Hounsell, E. F., (1996b). Comparison of separation modes for high-performance liquid chromatography of glycoprotein-and proteoglycan-derived oligosaccharides. J Chromatogr. 720:227–234.CrossRefGoogle Scholar
  10. Dustin, M.L., McCourt, D.W., and Kornfeld, S., 1996, A mannose 6-phosphate containing N-linked glycopeptide derived from lysosomal acid lipase is bound to MHC class II in B lymphoblastoid cell lines. J. Immunol. 156:1841–1847.PubMedGoogle Scholar
  11. Esko, J.D. and Zhang, L., 1996, Influence of core protein sequence on glycosaminoglycan assembly. Curr. Opin. Struct. Biol 6:663–670.PubMedCrossRefGoogle Scholar
  12. Fields, B.A., Malchiodi, EX., Li, H., Ysern, X., Stauffaeher, C.V., Schlievert, P.M., Karjalainen, K. and Mariuzza, R.A., 1996, Crystal structure of a T-cell receptor β-chain complexed with a superantigen. Nature 384:188–192.PubMedCrossRefGoogle Scholar
  13. Fukuda, M. 1996, Possible roles of tumour-associated carbohydrate antigens. Cancer Res. 56:2237–2244.PubMedGoogle Scholar
  14. Gallagher, J.T. 1995, Heparan sulphate and protein recognition. Binding specificities and activation mechanisms. Adv. Exp. Med. Biol. 376:125–34.PubMedCrossRefGoogle Scholar
  15. Garboczi, D.N., Ghosh, P., Utz, U., Fan, Q.R., Biddison, W.E., and Wiley, D.C., 1996, Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature, 384:134–141.PubMedCrossRefGoogle Scholar
  16. Haurum, J.S., Tan, L., Arsequell, G., Frodsham, P., Lellouch, A.C., Moss, P.A.H., Dwek, R.A., McMichael, A.J., and Elliott, T. (1995) Peptide anchor residue glycosylation: effect on class I major histocompatibility complex binding and cytotoxic T lymphocyte recognition. Eur. J. Immunol. 25:3270–3276.PubMedCrossRefGoogle Scholar
  17. Holland, S.J., Gale, N.W., Mbamalu, G., Yancopoulos, G.D., Henkemeyer, M and Pawson, T. 1996, Bidirectional signalling through the EPH-family receptor nuk and its transmembrane Ligands. Nature 383:722.PubMedCrossRefGoogle Scholar
  18. Hounsell, E.F. and Davies, M.J., 1993, Role of protein glycosylation in immune regulation. Annals Rheum. Dis. 52, S22–S29.CrossRefGoogle Scholar
  19. Hounsell, E.F., Davies, M.J. and Renouf, D.V., 1996, O-linked protein glycosylation structure and function. Glycoconjugate J. 13:19–26.CrossRefGoogle Scholar
  20. Hounsell, E.F. and Bailey, D., 1997, Approaches to the structure determination of oligosaccharides and glycopeptides using NMR. In Glycopeptides and related compounds: Synthesis, Analysis and Applications. Eds. D.G. Large and CD. Warren. Marcel Dekker Inc pp. 631–660.Google Scholar
  21. Hounsell, E.F., 1995, 1H-NMR in the Structural and Conformational Analysis of Oligosaccharides and Glycoconjugates. In Prog. NMR Spec, Eds. J.W. Emsley, J. Feeney and L.H. Sutcliffe, Elsevier 27:445–474.Google Scholar
  22. Hounsell, E.F., 1994, Physicochemical Analysis of Oligosaccharide Determinants of Glycoproteins. Adv. Carb. Chem. Biochem., 50:311–350.CrossRefGoogle Scholar
  23. Hyman, R., Lesley, J., Schulte, R., 1991, Somatic cell mutants distinguish CD44 expression and hyaluronic acid binding. Immunogenetics. 33:(5–6):392–5.PubMedCrossRefGoogle Scholar
  24. Kim, Y.S., Gum, J. jnr. and Brockhausen, I., 1996, Mucin glycoproteins in neoplasia. Glycoconj. J. 13: 693–707.PubMedCrossRefGoogle Scholar
  25. Larnkjær, A., Nykjær, A., Olivecrona, G., Thøgersen, H. and Østergaard, P.B., 1995, Structure of heparin fragments with high affinity for lipoprotein lipase and inhibition of lipoprotein lipase binding to α2-macroglobulin-receptor/low-density-lipoprotein-receptor-related protein by heparin fragments. Biochem. J. 307:205–214.PubMedGoogle Scholar
  26. Lehner, P.J. and Cresswell, P., 1996, Processing and delivery of peptides presented by MHC class I molecules. Curr. Opin. Immun. 8, 59–67.CrossRefGoogle Scholar
  27. Linhardt, R.J., Wang, H-M., Loganathan, D. and Bae, L-H., 1992, Search for the heparin antithrombin III-binding site precursor. J. Biol. Chem. 267:2380–2387.PubMedGoogle Scholar
  28. Massagué, J., 1996, Cross receptor boundaries. Nature, 382:29–30.PubMedCrossRefGoogle Scholar
  29. McConville, M. J. and Ferguson, M.A.J. 1993, The structure, biosynthesis and function of glycosylated phosphatidylinositols in the parasitic protozoa and higher eukaryotes. Biochem. J. 294:305–324.PubMedGoogle Scholar
  30. Niehrs, C., 1996, Mad connection to the nucleus, Nature, 381:561–562.PubMedCrossRefGoogle Scholar
  31. Otvos, L. jr., Krivulka, G.R., Urge, L., Szendrei, G.I., Nagy, L., Xiang, Z.Q., Ertl, H.C.J., 1995, Comparison of the effects of amino acid substitutions and β-N- vs. α-O-glycosylation on the T-cell stimulatory activity and conformation of an epitope on the rabies virus glycoprotein. Biochimica et Biophysica Acta, 1267:55–64.PubMedCrossRefGoogle Scholar
  32. Petty, H.R. and Todd III R. F., 1996, Integrins as promiscuous signal transduction devices. Trends Immunol. Today 17, 5:209–211.CrossRefGoogle Scholar
  33. Price, P., Allcock, R.J.N., Coombe, D.R., Shellam, G.R., McCluskey, J., 1995, MHC proteins and heparan sulphate proteoglycans regulate murine cytomegalovirus infection. Immunol. Cell Biol. 73:308–315.PubMedCrossRefGoogle Scholar
  34. Rider, C.C., Coombe, D.R., Harrop, H.A., Hounsell, E.F., Bauer, C.J., Feeney, J., Mulloy, B., Mahmood, N., and Parish, C.R. 1994, Anti-HIV-1 activity of chemically modified heparin: correlation between binding to the V3 loop of gp120 and inhibition of cellular HIV-1 infection in vitro. Biochem. 33:6974–6980.CrossRefGoogle Scholar
  35. Salmivirta, M., Lidholt, K., and Lindahl, U., 1996, Heparan sulfate: a piece of information, The FASEB J. 10:1270–1279.Google Scholar
  36. Scudder, P., Tang, P.W., Hounsell, E.F., Lawson, A.M., Mehmet, H. and Feizi, T. 1986, Isolation and characterisation of sulphated oligosaccharides released from bovine corneal keratan sulphate by endo-ß-galactosidase. Eur. J. Biochem., 157:365–373.PubMedCrossRefGoogle Scholar
  37. Smith, K.D., Bailey D.H., Davies M.J., Renouf, D.V., and Hounsell, E.F. 1996, Analysis of the glycosylation patterns of the extracellular domain of the epidermal growth factor expressed in Chinese hamster ovary fibroblasts. Growth Factors 13:1–12.CrossRefGoogle Scholar
  38. Stelter, F., Pfister, M., Berheiden, M., Jack, R., Bufler P. Engelmann, H. and Schutt, C., 1996, The myeloid differentiation antigen CD14 is N-and O-glycosylated. Contribution of N-linked glycosylation to different soluble CD 14 isoforms. Eur. J. Biochem, 236:457–464.PubMedCrossRefGoogle Scholar
  39. Tsuda, H., Yamada, S., Yamane, Y., Yoshida, K., Hopwood, J.J. and Sugahara, K., 1996, Structures of five sulfated hexasaccharides prepared from porcine intestinal heparin using bacterial heparinase. Structural variant with apparent biosynthetic precursor-product relationships for the antithrombin III-binding site. J. Biol Chem. 271:10495–10502.PubMedCrossRefGoogle Scholar
  40. Van Boeckel, CAA., Petitou, M. 1993, The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angew Chem Int. Ed 32:1671–1690.CrossRefGoogle Scholar
  41. Yamada, S., Sakamoto, K., Tsuda, H., Yamane, Y., Yoshida, K and Sugahara, K., 1996, Structural studies on the octasaccharide fraction prepared from porcine intestinal heparin after flavobacterium heparinase digestion. Proc. Milan 1996 Int. Curb Symp.Google Scholar
  42. Young, M., Davies, M.J. and Hounsell, E.F., 1996, Glycoprotein changes in tumours: a renaissance in clinical potential Nature Med. Submitted.Google Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Elizabeth F. Hounsell
    • 1
  • David V. Renouf
    • 1
  1. 1.Department of Biochemistry & Molecular BiologyUniversity College LondonLondonUK

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