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

Abstract

1 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 in®ltration of leukocytes in vivo. 2 OJ-R9188 prevented the binding of human E-, P-and L-selectin-IgG fusion proteins to immobilized sialyl Lewis x (sLe x )-pentasaccharide glycolipid, with IC 50 values of 4.3, 1.3, and 1.2 mM, respectively.3 In a mouse model of thioglycollate-induced peritonitis, OJ-R9188 at 10 mg kg 71 , i.v. inhibited neutrophil accumulation in the peritoneal cavity. In the IgE-mediated skin reaction, OJ-R9188 at 3 and 10 mg kg 71 , i.v. signi®cantly inhibited extravasation of neutrophils and eosinophils into the in¯ammatory sites and at 10 mg kg 71 , i.v. also inhibited in®ltration caused by picryl chlorideinduced 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-sLe x binding is a promising strategy for the treatment of allergic skin diseases.

Human CXCR2 (hCXCR2) takes over functionalities of its murine homolog in hCXCR2 knockin mice

“…Both wild‐type and hCXCR2 knockin mice were injected intraperitoneally with either PBS or thioglycollate. After 4 h, neutrophil influx into the peritoneum was determined by quantification of myeloperoxidase (MPO) activity, a biochemical marker for neutrophil infiltration 21, 22. In both thioglycollate‐treated wild‐type and hCXCR2 knockin animals, a significant increase of neutrophil infiltration was observed as compared to PBS‐treated animals (Fig.…”

“…MPO, a hemoprotein located in azurophil granules of neutrophils, has been used as a biochemical marker for neutrophil infiltration into tissues, including peritoneal cavity and skin 21, 22. Briefly, an aliquot (20 µL) of the supernatant and 180 µL 50 mM potassium phosphate buffer (pH 6.0) containing 0.167 mg/mL o‐dianisidine and 0.147 mM hydrogen peroxide were placed into a 96‐well plate and incubated for 30 min at room temperature.…”

Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

“…Biomosiamose (Retovar Biopharmaceuticals) is an effective pan-selectin inhibitor that attenuates late asthmatic reactions (Beeh et al, 2006) (Table 1). The synthetic selectin blocker ([N-(2-tetradecylhexadecanoyl)-O-(L-α-fucofucosyl)-D-seryl]-L-glutamic acid 1-methylamide 5-L-arginine salt, OJ-R9188) inhibits infiltration of leukocytes in an allergic dermatitis model in vivo (Ikegami-Kuzuhara et al, 2001).…”

Vascular adhesion and transendothelial migration of eosinophil leukocytes

“…This may be because eosinophils express Lselectin, but to a lower extent than neutrophils (Patel and McEver 1997;Juan et al 1999). L-selectin can also mediate intercellular interactions between leukocytes (Ikegami-Kuzuhara et al 2001). The L-selectin mAb has been shown to decrease the accumulation of eosinophils on human umbilical vein endothelial cells (HUVEC) by abrogating secondary tethers through interactions between flowing and attached eosinophils (Kitayama et al 1997a).…”

“…The major fragment that binds E-selectin on neutrophils is reported to be sialyl dimeric Lewis x . Other ligands for E-selectin include sialyl Lewis A (Miller et al 1996), cutaneous lymphocyte antigen (Ikegami-Kuzuhara et al 2001), E-selectin ligand-1, and myeloglycans (Kim et al 1998). The epitopes related to sialyl Lewis x are synthesized by α-1,3-fucosyltransferases (FucT).…”