Low molecular weight multivalent ligands have been designed to target the selectins, with most efforts focusing on E-selectin. Overall, these bi- or trisubstituted derivatives are slightly more effective than their monovalent counterparts in static binding assays, with typical affinity enhancements of three- to five-fold. For example, Defrees et al. used a chemoenzymatic approach to synthesize bivalent sialyl Lewis acid x derivatives in which the saccharides were linked by either a carbohydrate or other acyclic spacer . The most effective inhibitor of E-selectin in a static cell adhesion assay (inhibition of HL-60 cells binding to immobilized E-selectin) was that in which two sLex epitopes were linked through the 3- and 6-positions of galactose, 55 (Fig. 27). This ligand was approximately five-fold more potent than monovalent sLex. Ligands in which the sLex groups were tethered with more flexible polyethylene
Figure 27 Bivalent sLex ligands generated by Wong. The selectin epitopes were linked through the 3- and 6-positions of galactose (55) and via a polyethylene glycol chain (56).
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