SULFATED BLOOD-GROUP LEWIS(A) - A SUPERIOR OLIGOSACCHARIDE LIGAND FORHUMAN E-SELECTIN

In earlier studies of oligosaccharide probes (neoglycolipids) generate d from an ovarian cystadenoma glycoprotein, one of the components that strongly supported binding of the endothelial adhesion molecule, E-se lectin, was identified as an equimolar mixture of tetrasaccharides of blood group Le(a) and Le(x) type sulfated at position 3 of the outer g alactose (C.-T. Yuen, A. M. Lawson, W. Chai, M. Larkin, M. S. Stoll, A . C. Stuart, F. X. Sullivan, T. J. Ahern, and T. Feizi (1992) Biochemi stry 31, 9126-9131). In the present studies, the individual sulfated L e(a) and sulfated Le(x) oligosaccharides synthesized chemically have b een investigated, first, for their ability to support E-selectin bindi ng when converted into neoglycolipids, and second, for their ability t o inhibit E-selectin binding to immobilized lipid-linked sialyl-Le(a), sialyl-Le(x), or sulfated Le(a) pentasaccharides; their activities ha ve been compared with those of the sialyl-Le(a) and sialyl-Le(x) analo gues. From these studies, the sulfated Le(a) tetra- and pentasaccharid es emerge as the most potent E-selectin ligands so far. In particular, the inhibitory activity of the sulfated Le(a) pentasaccharide is subs tantially greater than that of the sialyl-Le(x) trisaccharide, which i s currently the most widely used inhibitor of E-selectin binding: 45-, 35-, or 15-fold greater depending on whether adhesion is to sialyl-Le( a), sulfated Le(a) or sialyl-Le(x) pentasaccharides, respectively. The se findings have an important bearing on design of new generations of inhibitors of E-selectin binding as anti-inflammatory compounds.