Recent Progress in the Design of Selectin Inhibitors

Chhabra, Siri Ram; Rahim, Aisyah Saad Abdul; Kellam, Barrie

doi:10.2174/1389557033487791

Cited by 16 publications

(11 citation statements)

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“…The standard galactosyltransferase reaction (25 l) contained 10 milliunits of purified bovine milk ␤1-4-galactosyltransferase (Sigma), 50 mM MES, pH 6.0, 0.3 Ci of UDP- [1][2][3] H]galactose, 250 M UDP-galactose, 15 mM MnCl 2 , 50 mM KCl, and varying amounts of deacetylated 1 as acceptor. After incubation at room temperature for 15 min, the reaction products were diluted with 1 ml of 0.5 M NaCl and applied to a Sep-Pak C18 (100 mg; Waters).…”

Section: Methodsmentioning

confidence: 99%

Deoxygenated Disaccharide Analogs as Specific Inhibitors of β1–4-Galactosyltransferase 1 and Selectin-mediated Tumor Metastasis

Brown

Yang

Sinha

et al. 2009

Journal of Biological Chemistry

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The disaccharide peracetylated GlcNAc␤1-3Gal␤-O-naphthalenemethanol (disaccharide 1) diminishes the formation of the glycan sialyl Lewis X (Neu5Ac␣2-3Gal␤1-4(Fuc␣1-3)GlcNAc; sLe X ) in tumor cells. Previous studies showed that the mechanism of action of disaccharide 1 involves three steps: (i) deacetylation by carboxyesterases, (ii) action as a biosynthetic intermediate for downstream enzymes involved in sLe X assembly, and (iii) generation of several glycans related to sLe X . In this report, we show that GlcNAc␤1-3Gal␤-O-naphthalenemethanol binds to the acceptor site of human ␤1-4-galactosyltransferase much like the acceptor trisaccharide, GlcNAc␤1-2Man␤1-6Man, which is present on N-linked glycans. The 4-deoxy analog, in which the acceptor hydroxyl group was replaced by -H, did not act as a substrate but instead acted as a competitive inhibitor of the enzyme. The acetylated form of this compound inhibited sLe X formation in U937 monocytic leukemia cells, suggesting that it had inhibitory activity in vivo as well. A series of synthetic acetylated analogs of 1 containing -H, -F, -N 3 , -NH 2 , or -OCH 3 instead of the hydroxyl groups at C-3-and C-4-positions of the terminal N-acetylglucosamine residue also blocked sLe X formation in cells. The reduction of sLe X by the 4-deoxy analog also diminished experimental tumor metastasis by Lewis lung carcinoma in vivo. These data suggest that nonsubstrate disaccharides have therapeutic potential through their ability to bind to glycosyltransferases in vivo and to alter glycan-dependent pathologic processes. . Although many of these analogs are effective in vitro, they generally do not exhibit inhibitory activity in cells due to poor membrane permeability. The large number of polar hydroxyl groups and the lack of membrane transporters for oligosaccharides in most cells presumably prevent their uptake (6).In contrast to many of the inhibitors described above, peracetylated disaccharides (e.g. acetylated Gal␤1-4GlcNAc␤-Onaphthalenemethanol (NM), acetylated Gal␤1-3GalNAc␣-O-NM, and acetylated GlcNAc␤1-3Gal␤-O-NM) inhibit sLe X biosynthesis in cells (6 -9). These compounds are taken up by cells by passive diffusion and acted on by cytoplasmic or membrane-associated carboxyesterases, which remove the acetyl groups. The compounds gain access to the biosynthetic enzymes located in the Golgi complex, where they serve as substrates, priming oligosaccharide synthesis and generating products related to O-GalNAc-linked mucin oligosaccharides. Priming in this manner diverts the assembly of the O-linked chains from endogenous glycoproteins, resulting in inhibition of expression of terminal Lewis antigens that are recognized by * This work was supported, in whole or in part, by National Institutes of Health Grants CA46462 and CA112278 (to J. D. E.) and by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. The crystallographic part of this project has been funded, in whole or in part, with federal funds from NCI, National Institutes of...

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Section: Methodsmentioning

confidence: 99%

Deoxygenated Disaccharide Analogs as Specific Inhibitors of β1–4-Galactosyltransferase 1 and Selectin-mediated Tumor Metastasis

Brown

Yang

Sinha

et al. 2009

Journal of Biological Chemistry

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“…These include (i) competition by glycolipids and soluble recombinant forms of selectins and glycoprotein ligands, (ii) peptides based on the primary sequence of the carbohydrate binding site, (iii) anti-selectin antibodies, (iv) oligosaccharides related to Le A and Le X , (v) inositol polyanions and sulfated sugars, (vi) heparin, and (vii) molecular mimics of sLe X , including oligonucleotides (for a review, see (Chhabra et al, 2003). This approach has much appeal since pharmacological blockade of protein-carbohydrate interactions can be initiated quickly by intravenous injection of the inhibitor.…”

Section: Blocking O-glycan-protein Interactionsmentioning

confidence: 99%

Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Brown¹,

Crawford²

2007

Critical Reviews in Biochemistry and Molecular Biology

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Glycans, the carbohydrate chains of glycoproteins, proteoglycans, and glycolipids, represent a relatively unexploited area for drug development compared with other macromolecules. This review describes the major classes of glycans synthesized by animal cells, their mode of assembly, and available inhibitors for blocking their biosynthesis and function. Many of these agents have proven useful for studying the biological activities of glycans in isolated cells, during embryological development, and in physiology. Some are being used to develop drugs for treating metabolic disorders, cancer, and infection, suggesting that glycans are excellent targets for future drug development.

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“…Various strategies have been applied to reduce the sLex structure to the essential pharmacophoric moieties by replacing carbohydrates in order to get more simple mimetics of higher affinity. These strategies are excellently reviewed in recent papers [10][11][12].…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Inhibitors of Membrane Receptors Involved with Leukocyte Extravasation

Bendas

2005

MRMC

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The migration of leukocytes from the blood stream to sites of infection is a key event in cellular immune response, mediated by multiple types of molecules including several adhesion receptors. The inhibition of adhesion receptors holds great promise for novel therapeutical strategies to treat chronic inflammatory disorders or autoimmune diseases. This review reports on recent advances in adhesion-based therapeutics and focuses on structural classification of selectin and integrin inhibitors.

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Recent Progress in the Design of Selectin Inhibitors

Cited by 16 publications

References 0 publications

Deoxygenated Disaccharide Analogs as Specific Inhibitors of β1–4-Galactosyltransferase 1 and Selectin-mediated Tumor Metastasis

Deoxygenated Disaccharide Analogs as Specific Inhibitors of β1–4-Galactosyltransferase 1 and Selectin-mediated Tumor Metastasis

Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Inhibitors of Membrane Receptors Involved with Leukocyte Extravasation

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