Therapeutic potential of a novel synthetic selectin blocker, OJ-R9188, in allergic dermatitis

Abstract

We investigated the ability of a newly synthesized sugar derivative, OJ-R9188, (N-(2-tetradecylhexadecanoyl)-O-(L-alpha-fucofuranosyl)-D-seryl)-L-glutamic acid 1-methylamide 5-L-arginine salt, to block binding of selectins to their ligands in vitro and inhibit the infiltration of leukocytes in vivo. OJ-R9188 prevented the binding of human E-, P- and L-selectin-IgG fusion proteins to immobilized sialyl Lewis↑ (sLex)-pentasaccharide glycolipid, with IC50 values of 4.3, 1.3, and 1.2 μM, respectively. In a mouse model of thioglycollate-induced peritonitis, OJ-R9188 at 10 mg kg-1, i.v. inhibited neutrophil accumulation in the peritoneal cavity. In the IgE-mediated skin reaction, OJ-R9188 at 3 and 10 mg kg-1, i.v. significantly inhibited extravasation of neutrophils and eosinophils into the inflammatory sites and at 10 mg kg-1, i.v. also inhibited infiltration caused by picryl chloride-induced delayed-type hypersensitivity in mice. These results suggest that OJ-R9188 may be a useful selectin blocker, with activity against human and mouse E-, P- and L-selectins in vitro and in vivo, and that blocking selectin-sLex binding is a promising strategy for the treatment of allergic skin diseases.