Peptide inhibitors of selectin binding

Details Peptide inhibitors of selectin binding Peptide inhibitors of selectin binding

1995-06-09

1998-01-20

Jones, W. Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 9, 514 15, 530300, 530317, 530321, 530328, 530333, 530334, A01N 3718, A61K 3800, C07K 500, C07K 700

Patent

active

057101230

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to peptides which inhibit binding of selectins such as P-selectin, E-selectin and L-selectin.
The adherence of platelets and leukocytes to vascular surfaces is a critical component of the inflammatory response and is part of a complex series of reactions involving the simultaneous and interrelated activation of the complement, coagulation, and immune systems.
The complement proteins collectively play a leading role in the immune system, both in the identification and in the removal of foreign substances and immune complexes, as reviewed by Muller-Eberhard, H. J., Ann. Rev. Biochem. 57: 321-347 (1988). Central to the complement system are the C3 and C4 proteins, which when activated covalently attach to nearby targets, marking them for clearance. In order to help control this process, a remarkable family of soluble and membrane-bound regulatory proteins has evolved, each of which interacts with activated C3 and/or C4 derivatives. The coagulation and inflammatory pathways are regulated in a coordinate fashion in response to tissue damage. For example, in addition to becoming adhesive for leukocytes, activated endothelial cells express tissue factor on the cell surface and decrease their surface expression of thrombomodulin, leading to a net facilitation of coagulation reactions on the cell surface. In some cases, a single receptor can be involved in both inflammatory and coagulation processes.
Leukocyte adherence to vascular endothelium is a key initial step in migration of leukocytes to tissues in response to microbial invasion. Although a class of inducible leukocyte receptors, the CD11-CD18 molecules, are thought to have some role in adherence to endothelium, mechanisms of equal or even greater importance for leukocyte adherence appear to be due to inducible changes in the endothelium itself.
Activated platelets have also been shown to interact with both neutrophils and monocytes in vitro. The interaction of platelets with monocytes may be mediated in part by the binding of thrombospondin to platelets and monocytes, although other mechanisms have not been excluded. The mechanisms for the binding of neutrophils to activated platelets are not well understood, except that it is known that divalent cations are required. In response to vascular injury, platelets are known to adhere to subendothelial surfaces, become activated, and support coagulation. Platelets and other cells may also play an important role in the recruitment of leukocytes into the wound in order to contain microbial invasion.
Endothelium exposed to "rapid" activators such as thrombin and histamine becomes adhesive for neutrophils within two to ten minutes, while endothelium exposed to cytokines such as tumor necrosis factor and interleukin-1 becomes adhesive after one to six hours. The rapid endothelial-dependent leukocyte adhesion has been associated with expression of the lipid mediator platelet activating factor (PAF) on the cell surface, and presumably, the appearance of other endothelial surface receptors. The slower cytokine-inducible endothelial adhesion for leukocytes is mediated, at least in part, by E-selectin that is synthesized by endothelial cells after exposure to cytokines and then transported to the cell surface, where it binds neutrophils. The isolation, characterization and cloning of E-selectin or ELAM-1 is reviewed by Bevilacqua, et al., in Science 243, 1160-1165 (1989). L-selectin, a peripheral lymph node homing receptor, also called "the murine Mel 14 antigen", "Leu 8", the "Leu 8 antigen" and "LAM-1", is another structure on neutrophils, monocytes, and lymphocytes that binds lymphocytes to high endothelial venules in peripheral lymph nodes. The characterization and cloning of the protein is reviewed by Lasky, et al., Cell 56, 1045-1055 (1989) (mouse) and Tedder, et al., J. Exp. Med. 170, 123-133 (1989).
P-selectin, also known as GMP-140 (granule membrane protein 140), or PADGEM, is a cysteine-rich and heavily glycosylated integral membrane glycoprotein with an apparen

REFERENCES:
patent: 3625214 (1971-12-01), Higuchi
patent: 4789734 (1988-12-01), Pierschbacher
patent: 4906474 (1990-03-01), Langer et al.
patent: 4925673 (1990-05-01), Steiner et al.
patent: 5116964 (1992-05-01), Capon et al.
patent: 5192746 (1993-03-01), Lobl et al.
patent: 5198424 (1993-03-01), McEver
patent: 5440015 (1995-08-01), Macher et al.
patent: 5444050 (1995-08-01), Kogan et al.
patent: 5464935 (1995-11-01), Heavner et al.
patent: 5602230 (1997-02-01), Heavner et al.
patent: 5618785 (1997-04-01), Heavner et al.
Abbott, S.E. et al., "Isolation and culture of synovial microvascular endothelial cells", Arthritis and Rheumatism 1992, 35(4), 401-406.
Ager, A. and Humphries, M.J., "Use of synthetic peptides to probe lymphocyte- high endothelial cell interactions. Lymphocytes recognize a ligand on the endothelial surface which contains the CS1 adhesion motif", International Immunology 1990, 2 (10), 921-928.
Albelda, S.A. and Buck, C.A., "Integrins and other cell adhesion molecules", FASEB 1990, 4, 2868-2880.
Albelda, S.A., "Endothelial and epithelial cell adhesion molecules", Am. J. Respir. Cell Mol. Biol. 1991, 4, 195-203.
Aruffo, A. et al., "CD62/P-selectin recognition of myeloid and tumor cell sulfatides", Cell 1991, 67, 35-44.
Aruffo, A. et al., "Granule membrane protein 140 (GMP140) binds to carcinomas and carcinoma-derived cell lines", PNAS USA 1992, 89, 2292-2296.
Ball, G.E. et al., "Synthesis and structural analysis using 2-D NMR of sialyl Lewis X (SLe.sup.x) and Lewis Le.sup.x) oligosaccharides: ligands 114, 5449-5451.
Bennett, J.S., "The molecular biology of platelet membrane proteins", Seminars in Hematology 1990, 27(2), 186-204.
Berg, M. and James, S.P., "human neutrophils release the leu-8 lymph node homing receptor during cell activation", Blood 1990, 76(11), 2381-2388.
Berg, E.L. et al., "A carbohydrate domain common to both Sialyl Le.sup.a and Sialyl Le.sup.x is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1", J. of Biological Research Communications 1992, 266 (23), 14869-14872.
Berg, E.L. et al., "Comparison of L-selectin and E-selectin ligand specificities: the L-selectin can bind the E-selectin ligands SIALYL Le.sup.x and SIALYL Le.sup.a ", Biochemical and Biophysical Research Communications 1992, 184 (2), 1048-1055.
Bevilacqua, M. et al., "Endothelial leukocyte adhesion molecule 1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins", Science 1989, 243, 1160-1165.
Bevilacqua, M. et al., "Selectins: a family of adhesion receptors", Cell 1991, 67, 233.
Bevilacqua, M. et al., "Identification of an inducible endothelial-leukocyte adhesion molecule", Proc. Natl. Acad. Sci. USA 1987, 84: 9238-9242.
Bodanszky, M. et al., "Peptide Synthesis", 2nd edition, John Wiley & Sons, 1976.
Bradley, L.M. et al., "Long-term CD4.sup.+ memory T cells fron the spleen lack mel-14, the lynmph node homing receptor", J. of Immunology 1992, 148(2), 324-331.
Brandley, B.K. et al., "Carbohydrate ligands of the LE cell adhesion molecules", Cell 1990, 63, 861-863.
Brown, E. et al., "Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins", J. of Cell Biology 1990, 111 (6), 2785-2794.
Buhrer, C. et al., "Lymphocyte activation and regulation of three adhesion molecules with supposed function in homing: LECAM-1 (MEL-14 Antigen), LPAM-1/2 (.alpha..sup.4 -integrin) and CD44 (Pgp-1)", Scandinavian J. of Immunology 1992, 35, 107-120.
Camerini, D. et al., "Leu-8/TQ1 is the human equivalent of the Mel-14 lymph node homing receptor", Nature 1989, 342, 78-82.
Carmody, M.W. et al. , "Production of monoclonal antibodies secific for platelet activation antigens and their use in evaluating platelet function", Hybridoma 1990, 9(6), 631-641.
Celi, A. et al., "PADGEM: an adhesion receptor for leukocytes on stimulated platelets and endothelial cells", Procedures of the Society of Experimental and Biological Medicine 1991, 198(2), 703-709.
Corral, L. et al. , "Requ

Affiliated with

Also associated with

Rating

Peptide inhibitors of selectin binding does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Peptide inhibitors of selectin binding, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptide inhibitors of selectin binding will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-725347