Studies on Selectin Blocker. 1. Structure−Activity Relationships of Sialyl Lewis X Analogs

Ohmoto, Hiroshi; Nakamura, Kenji; Inoue, Tomomi; Kondo, Noriko; Inoue, Yoshimasa; Yoshino, Kohichiro; Kondo, Hirosato; Ishida, Hideyuki; Kiso, Makoto; Hasegawa, Akira

doi:10.1021/jm9506478

Cited by 57 publications

(39 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…sialyl Lewis X ceramide, NeuAc␣2-3Gal␤1-4(Fuc␣1-3)(SO 4 -6) GlcNAc␤1-3Gal␤1-4Glc␤1-Cer; 6Ј-sulfo sialyl Lewis X ceramide, NeuAc␣2-3(SO 4 -6)Gal␤1-4(Fuc␣1-3)GlcNAc␤1-3Gal␤1-4Glc␤1-Cer; 6,6Ј-bis-sulfo sialyl Lewis X ceramide, NeuAc␣2-3(SO 4 -6)Gal␤1-4(Fuc␣1-3)(SO 4 -6)GlcNAc␤1-3Gal␤1-4Glc␤1-Cer (25)(26)(27). The asialo compounds were prepared by digestion with neuraminidase from Arthrobacter ureafaciens (Nakalai Tesque).…”

Section: Materials-thementioning

confidence: 99%

“…The sequence around the putative first ATG codon conformed to Kozak's rule (40), and the upstream region contained an in-frame stop codon. Hydropathy analysis indicated one prominent hydrophobic segment 20 residues in length in the amino-terminal region (Ala 8 -Leu 27 ), predicting that the protein has type II transmembrane topology (Fig. 1B).…”

Section: Molecular Cloning Of a Cdnamentioning

confidence: 99%

See 1 more Smart Citation

Molecular Cloning and Characterization of anN-Acetylglucosamine-6-O-sulfotransferase

Uchimura¹,

Muramatsu²,

Kadomatsu³

et al. 1998

Journal of Biological Chemistry

151

111

View full text Add to dashboard Cite

We isolated a cDNA clone encoding mouse N-acetylglucosamine-6-O-sulfotransferase based on sequence homology to the previously cloned mouse chondroitin 6-sulfotransferase. The cDNA clone contained an open reading frame that predicts a type II transmembrane protein composed of 483 amino acid residues. The expressed enzyme transferred sulfate to the 6 position of nonreducing GlcNAc in GlcNAc␤1-3Gal␤1-4GlcNAc. Gal␤1-4GlcNAc␤1-3Gal␤1-4GlcNAc and various glycosaminoglycans did not serve as acceptors. Expression of the cDNA in COS-7 cells resulted in production of a cell-surface antigen, the epitope of which was NeuAc␣2-3Gal␤1-4(SO 4 -6)GlcNAc; double transfection with fucosyltransferase IV yielded Gal␤1-4(Fuc␣1-3)(SO 4 -6)GlcNAc antigen. The sulfotransferase mRNA was strongly expressed in the cerebrum, cerebellum, eye, pancreas, and lung of adult mice. In situ hybridization revealed that the mRNA was localized in high endothelial venules of mesenteric lymph nodes. The sulfotransferase was concluded to be involved in biosynthesis of glycoconjugates bearing the 6-sulfo N-acetyllactosamine structure such as 6-sulfo sialyl Lewis X. The products of the sulfotransferase probably include glycoconjugates with intercellular recognition signals; one candidate of such a glycoconjugate is an L-selectin ligand.

show abstract

Section: Materials-thementioning

confidence: 99%

Section: Molecular Cloning Of a Cdnamentioning

confidence: 99%

Molecular Cloning and Characterization of anN-Acetylglucosamine-6-O-sulfotransferase

Uchimura¹,

Muramatsu²,

Kadomatsu³

et al. 1998

Journal of Biological Chemistry

151

111

View full text Add to dashboard Cite

show abstract

“…An enzyme‐linked immunosorbent assay (ELISA) was performed in microtiter plates (96 wells, PRO‐BIND) coated with sLe X pentaceramides as reported previously 10. Both the polymeric 6 – 9 and monomeric ligands 3 a – 5 a were assayed in the same way to evaluate the effect of multivalent binding on their ability to block L‐selectin.…”

Section: Methodsmentioning

confidence: 99%

Facile Assembly of Cell Surface Oligosaccharide Mimics by Copolymerization of Carbohydrate Modules

Sasaki

Nishida

Tsurumi

et al. 2002

Angewandte Chemie Intl Edit

Self Cite

View full text Add to dashboard Cite

Artificial glycoconjugate polymers (glycopolymers) and other multivalent carbohydrate ligands constitute a new class of biomimetic supramolecules. [1] They have shown many biological applications in, for example, cultivation, tumor diagnosis and detection, and the trapping of viruses and bacterial toxins. [2] Their utility is ascribed mainly to their strong and species-specific interactions with the receptor proteins as a result of multivalent binding and/or carbohydrate cluster effects. Although most of the glycopolymers so far prepared and applied were made up of simple mono-and disaccharides, more intense interest has been directed to glycopolymers carrying cell-surface oligosaccharides such as sialyl Lewis X (sLe X ) [3] and globosyl oligosaccharides [4] that have potentially greater biological significance. From a practical viewpoint, however, the synthesis and application of these glycoconjugates are seriously restricted by the difficulty in preparing target oligosaccharides in sufficient amounts prior to their incorporation into the multivalent models.In the course of our synthetic study of glycopolymers carrying the mimics of cell-surface oligosaccharides, [5] we found recently that an acrylamide copolymer carrying a-l-fucopyranoside and 3-sulfo-b-d-galactopyranoside as a side chain shows strong activity in blocking L-selectin/sLe X tetrasaccharide adhesion. [6] As judged from the observation that none of the acrylamide copolymers carrying only one of the two glycosides showed a notable activity, the observed activity was ascribed to the cooperative binding of the a-lfucoside and 3-sulfo-b-d-galactoside to L-selectin. This finding indicated the potential utility of the module approach and prompted us to generalize it as a ™carbohydrate module method∫.For the facile understanding of our ™carbohydrate module method∫, let us assume a model consisting of the binding of a branching pentasaccharide with the receptor protein (Figure 1). In this model the two glycoside residues (A1 and A2) at the nonreducing terminal provide key binding interactions with the receptor protein at the r(A1) and r(A2) binding sites. Conventional mimic syntheses may target a branching trisaccharide carrying A1, A2, and B residues, thus developing the multivalent model (polymer-(A1 þ A2 þ B)) in Figure 1 b. Our approach targets a copolymer-(A1/A2) species carrying the key interactive sugars (Figure 1 c) to circumvent the difficulty in preparing the branching saccharide. The copolymer-(A1/A2) species is assumed to have a certain probability of occupying both of the binding sites and, thus, is expected to show a higher binding activity than the polymers carrying only one of the key sugars (poly-(A1) and poly-(A2)). This situation means that copolymerization of two key interactive sugars (A1 and A2 in the present case) provides a facile way to mimic the biologically active structures of oligosaccharides. The glycopolymers thus derived may show potent biological activity in blocking the binding of the oligosaccharide to receptor proteins...

show abstract

“…(1992). The construction, expression and purification of human and mouse E‐, P‐ and L‐selectin Ig were carried out as described previously (Ohmoto et al ., 1996). Aliquots (50 μl; 100 pmol) of sLe x ‐pentasaccharide ceramide in 50% methanol were placed into microplate wells (96‐well plates; Falcon Pro‐Bind (Becton Dickinson, Franklin Lakes, NJ, U.S.A.) and the solvent was evaporated.…”

Section: Methodsmentioning

confidence: 99%

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

Ikegami-Kuzuhara¹,

Yoshinaka²,

Ohmoto³

et al. 2001

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Studies on Selectin Blocker. 1. Structure−Activity Relationships of Sialyl Lewis X Analogs

Cited by 57 publications

References 28 publications

Molecular Cloning and Characterization of anN-Acetylglucosamine-6-O-sulfotransferase

Molecular Cloning and Characterization of anN-Acetylglucosamine-6-O-sulfotransferase

Facile Assembly of Cell Surface Oligosaccharide Mimics by Copolymerization of Carbohydrate Modules

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

Contact Info

Product

Resources

About