Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-09-03
1998-10-27
Huang, Evelyn
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514126, 514517, A61K 3166
Patent
active
058278370
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the field of cell adhesion molecules and specifically to the use of inositol polyanion compositions for modulating selectin binding.
2. Description of Related Art
Cell adhesion molecules (CAMs) play a role in inflammation, infection, cancer and other disease processes. Recent advances in cloning and protein sequencing have led to the organization of CAMs into families, based on their molecular structure. Intense research has been focused on selectins, which are carbohydrate-binding proteins expressed on endothelial and leukocyte cell surfaces; integrins, which are found on the surfaces of leukocytes; and proteins of the immunoglobulin type such as intracellular adhesion molecule, ICAM-1 and 2 which occur on many different cell surfaces.
The mechanism of inflammation can be understood in terms of CAM interactions. Leukocyte adhesion to the vessel wall is a key step in the development of inflammatory and immunological processes. Adhesion molecules that support these interactions include the selecting, a group of CAMs which are named for the cell type on which they were originally identified. The selectins include E-selectin (endothelial cells), P-selectin (platelets) and L-selectin (lymphocytes).
The three selectins act in concert with other cell adhesion molecules (e.g., ICAM-1, vascular cell adhesion molecule-1 and the leukocyte integrins) to effect adhesive interactions of leukocytes, platelets and endothelial cells. E-selectin was first shown to support the adhesion of neutrophils to cytokine-activated endothelium (Bevilacqua, et al., Proc. Natl. Acad. Sci., USA. 84:9238, 1987; Bevilacqua, et al., Science 243:1160, 1989). Subsequent studies in vitro have suggested that E-selectin also supports the binding of monocytes, a subpopulation of memory T lymphocytes, eosinophils and basophils. Similarly, P-selectin also supports leukocyte adhesion. In addition to its role in lymphocyte homing, L-selectin appears to participate in the adhesion of neutrophils, monocytes and lymphocytes to activated endothelium (reviewed in Bevilacqua, M. and Nelson, R., J.Clin. Invest. 91:379, 1993).
Each selectin is a transmembrane glycoprotein containing an N-terminal lectin-like domain, an epidermal growth factor repeat, and a discrete number of complement regulatory-like repeats. E- and P-selectin are expressed by activated endothelial cells while L-selectin is constitutively expressed on leukocytes and can be shed upon activation. E- and P-selectin recognize oligosaccharide structures including the tetrasaccharide, sialyl Lewis.sup.x (sLe.sup.x ; Neu5Ac.alpha.2-3Gal.beta.1-4(Fuc.alpha.1-3)GIcNAc) that are found on leukocytes. L-selectin can bind similar structures, although recent studies suggest a substantial difference in affinities. In addition, L-selectin has been shown to bind sulfatides (sulfated glycolipids) as well as sulfate-and sialic acid-containing mucin-type glycoproteins expressed on high endothelial venules of lymph nodes. Soluble oligosaccharides related to sLe.sup.x and sLe.sup.a (a positional isomer of sLe.sup.x) are able to inhibit ligand binding and adhesive functions of E- and P-selectin. These compounds have been under investigation as anti-inflammatory agents, however, their complex structures pose significant obstacles for large-scale synthesis. Previous studies have shown that phosphate- and sulfate-containing carbohydrates unrelated to sLe.sup.x can interact with P- and L-selectin. For example, PPME, the poly-phosphomonoester core of Hansenula holstil O-phosphonomannan, blocks L-selectin dependent adhesion. In addition, fucoidan, a sulfated polysaccharide produced by brown algae, and heparin, a sulfated glycosaminoglycan produced by mast cells, interact with both P- and L-selectin. Finally, high concentrations (typically, 5-10 mM) of phosphated monosaccharides have been shown to block P- and L-selectin dependent adhesion in vitro.
Inositol polyanions are derivatives of a six carbon ring structure (1,2,3,5-trans
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Bevilacqua Michael P.
Cecconi Oliviero
Nelson Richard M.
Huang Evelyn
The Regents of the University of California
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