Sulfated blood group Lewis(a). A superior oligosaccharide ligand for human E-selectin.
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 Le(a) 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 Le(a) 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-Le(a), sialyl-Le(x), or sulfated Le(a) pentasaccharides; their activities have been compared with those of the sialyl-Le(a) and sialyl-Le(x) analogues. From these studies, the sulfated Le(a) tetra- and pentasaccharides emerge as the most potent E-selectin ligands so far. In particular, the inhibitory activity of the sulfated Le(a) 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-Le(a), sulfated Le(a), or sialyl-Le(x) pentasaccharides, respectively. These findings have an important bearing on design of new generations of inhibitors of E-selectin binding as antiinflammatory compounds.
Yuen
C T
CT
Glycoconjugates Section, Medical Research Council Clinical Research Centre, Harrow, Middlesex, United Kingdom.
Bezouska
K
K
O'Brien
J
J
Stoll
M
M
Lemoine
R
R
Lubineau
A
A
Kiso
M
M
Hasegawa
A
A
Bockovich
N J
NJ
Nicolaou
K C
KC
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D019040:E-Selectin; D006801:Humans; D007983:Lewis Blood Group Antigens / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D013431:Sulfates / Q000032:analysis*; D014162:Transfection
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007983:Lewis Blood Group Antigens; D009844:Oligosaccharides; D013431:Sulfates