Sialylated oligosaccharides, selectins

The synthesis of a collection of sulfated or sialylated oligosaccharides has confirmed that sulfates are the best inhibitors. The most active is the sulfated pentasaccharide 17.31 which is, until the present, the best ligand known of E-selectin, giving 50% inhibition at the very low concentration of 5 x 10 M (Lubineau et al. 1994). 

The precise chemical nature of some of the ligands involved in selectin-ligand interactions has been determined. All three selectins bind sialylated and fucosy-lated oligosaccharides, and in particular all three bind sialyl-Lewis (Figure 47-12), a structure present on both glycoproteins and glycolipids. Whether this compound is the actual ligand involved in vivo is not estab-... 

Carbohydrate-mediated cell adhesion is an important event which can be initiated by tissue injury or infection and is involved in metastasis. One such adhesion process is the interaction between the glycoprotein E-selectin and oligosaccharides on the surface of neutrophils (white blood cells). The ligand that E-selectin recognizes is the tetrasaccharide sialyl Lewis X (SLe ). Since SLe competes with white blood cells for binding to E-selectin, thus inhibiting the adhesion process, it may useful as an anti-inflammatoiy and anticancer agent. 

C. Foxall, S. R. Watson, D. Dowbenko, C. Fennie, L. A. Lasky, M. Kiso, A. Hasegawa, D. Asa, and B. K. Brandley, The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis X oligosaccharide, J. Cell Biol. 7/7 895 (1992). 

M. Larkin, T. J. Ahem, M. S. Stoll, M. Shaffer, D. Sako, J. O Brien, C.-T. Yuen, A. M. Lawson, R. A. Childs, K. M. Barone, P. R. Langer-Safer, A. Hasegawa, M. Kiso, G. R. Larsen, and T. Feizi, Spectrum of sialylated and nonsialylated fuco-oligosaccharides bound by the endothelial-leukocyte adhesion molecule E-selectin, J. Biol. Chem. 267 13661 (1992). 

Ng, K. K.-S., Weis, W I, Stmcture of a selectin-like mutant of mannose-binding protein complexed with sialylated and sulfated Lewis oligosaccharides. Biochemistry, 36, 979-988, 1997. 

Ill. Norgard, K E, Moore, K L, Diaz, S, Stubs, N L, Ushiyama, S, McEver, R P, Cummings, R D, Varki, A, Characterization of a specific ligand for P-selectin on myeloid cells. A minor glycoprotein with sialylated 0-linked oligosaccharides, J. Biol. Chem., 268, 12764-12774, 1993. 

More recently, multivalent approaches [328,329,330] were reported. Based on molecular modeling approaches, non-sugar sLe mimetics [331,332,333] such as 107 (IC5o = 86, 6.1, and 30 jM for E-, P- and L-selectins respectively) [331] were created. A peptide mimicking the sialyl Lewis oligosaccharide has been identified [334], this concept is discussed in more detail the next chapter. 

The involvement of sialic acid in the interaction of leukocyte adhesion receptors of the selectins with their ligands has been a subject of numerous reviews. It is obvious from these studies that sialic acid is involved in this interaction because of the charge of its carboxylic group that can be substituted with sulfate [220]. More recently, selectin/mannose-binding protein chimeras have been constructed to understand the mechanism involved in the binding of sialylated Lexis oligosaccharide by this receptor [221]. 

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