Sulfated blood group Lewisa. A superior oligosaccharide ligand for human E-selectin

Abstract

In earlier studies of oligosaccharide probes (neoglycolipids) generated from an ovarian cystadenoma glycoprotein, one of the components that strongly supported binding of the endothelial adhesion molecule, E-selectin, was identified as an equimolar mixture of tetrasaccharides of blood group Lea and Le(x) type sulfated at position 3 of the outer galactose (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) Biochemistry 31, 9126-9131). In the present studies, the individual sulfated Lea and sulfated Le(x) oligosaccharides synthesized chemically have been investigated, first, for their ability to support E-selectin binding when converted into neoglycolipids, and second, for their ability to inhibit E-selectin binding to immobilized lipid-linked sialyl-Lea, sialyl-Le(x), or sulfated Lea pentasaccharides; their activities have been compared with those of the sialyl-Lea and sialyl-Le(x) analogues. From these studies, the sulfated Lea tetra- and pentasaccharides emerge as the most potent E-selectin ligands so far. In particular, the inhibitory activity of the sulfated Lea pentasaccharide is substantially greater than that of the sialyl-Le(x) trisaccharide, which is currently the most widely used inhibitor of E-selectin binding: 45-, 35-, or 15-fold greater depending on whether adhesion is to sialyl-Lea, sulfated Lea ,or sialyl-Le(x) pentasaccharides, respectively. These findings have an important bearing on design of new generations of inhibitors of E-selectin binding as anti-inflammatory compounds.