Synergistic interactions of the two classes of ligand, sialyl‐Lewisa/x fuco‐oligosaccharides and short sulpho‐motifs, with the P‐ and L‐selectins: implications for therapeutic inhibitor designs

Publisher Website
Google Scholar
Abstract
Summary: The E‐, L‐ and P‐selectins are carbohydrate‐recognizing cell‐adhesion molecules mediating selective leucocyte recruitment in inflammation. The 3′‐sialyl‐ and 3′‐sulpho‐oligosaccharides of Lewisx (Lex) and Lewisa (Lea) series are bound by them, but for high‐avidity binding of P‐ and L‐selectins to the glycoprotein counter‐receptor known as P‐selectin glycoprotein ligand, PSGL‐1, there is a requirement for sulpho‐tyrosines neighbouring a sialyl‐Lex glycan. The two selectins can also bind 3‐O‐ or 6‐O‐sulphated galacto‐lipids (sulphatides). Here we compare some features of the interactions of P‐ and L‐selectins with a novel lipid‐linked sulpho‐tyrosine probe, and with the sulphatides and neoglycolipids of sialyl‐ and sulpho‐Lex/Lea fuco‐oligosaccharides. The sulpho‐tyrosine probe is bound by both selectins. There are close similarities in the interactions of the two selectins with sulpho‐tyrosine and the sulphatides; the binding is relatively resistant to chelation of calcium ions, in contrast to the absolute requirement of calcium ions with the long fuco‐oligosaccharides, including 6‐sulpho‐sialyl‐Lex. With both selectins, there is striking synergy in binding signals elicited by the two ligand types when presented as equimolar mixtures on a matrix. Thus, there are two operationally distinct binding sites on both L‐ and P‐selectin; and the binding sites for sulphate groups in the two ligand types are probably distinct. When sulpho‐tyrosine and sialyl‐Lex are presented on liposomes, a potent inhibitory activity is generated toward the binding of P‐selectin to HL60 cells, with 50% inhibitory concentration (IC50) values in the nanomolar range. These features of the lipid‐linked ligand analogues, and the simple approach for their display on liposomes, may have applications in designs and screening of selectin inhibitors as anti‐inflammatory compounds.

This publication has 51 references indexed in Scilit: