Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-01-06
2000-03-07
Celsa, Bennett
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 11, 514 16, 530317, 530328, A41K 3812, C07K 512
Patent
active
060340576
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
1. Field of the Invention
Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, vitronectin and VCAM-1) and their integrin receptors [e.g. VLA-4 ((.alpha.4.beta.1)]. Recent studies have shown these interactions to play an important role in many physiological (e.g. embryonic development and wound healing) and pathological (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune diseases) conditions. Agents which can selectively inhibit some of these interactions are predictably useful for the treatment of a number of diseases.
Integrins are heterodimeric cell surface receptors that are composed of noncovalently associated .alpha. and .beta. subunits. Using molecular biology and protein chemistry, a number of .alpha. and .beta. subunits have been identified. The integrin family can be subdivided into classes based on the .beta. subunits, which can be associated with one or more .alpha. subunits. The most widely distributed integrins belong to the .beta.1 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte-specific receptors and consist of one of three .alpha. subunits (.alpha.L, .alpha.M, or .alpha.X) complexed with the .beta.2 protein. The cytoadhesins .alpha.IIb.beta.3 and .alpha.v.beta.3, constitute the third class of integrins.
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins, and cell surface molecules. Extracellular matrix proteins such as collagen, fibronectin, fibrinogen, laminin, thrombospondin, and vitronectin bind to a number of integrins. Many of these adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell-bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
2. Description of the Related Art
The target amino acid sequences for many integrins have been identified. For example, the target sequence in .alpha.5.beta.1, .alpha.II.beta.3, and .alpha.v.beta.3, is the Arg-Gly-Asp tripeptide found in proteins such as fibronectin, fibrinogen, thrombospondin, type I collagen, vitronectin and vWF. However, the Arg-Gly-Asp sequence is not the only integrin recognition motif used by adhesive ligands. Another integrin .alpha.4.beta.1 binds the variable region (CS1) of fibronectin via the sequence Leu-Asp-Val and the platelet integrin .alpha.IIb.beta.3 also recognises the sequence His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val at the carboxy-terminus of the gamma chain of fibrinogen.
The present invention principally relates to agents which block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (.alpha.4.beta.1). [Reference for a review on VLA-4: Structure of the Integrin VLA-4 and Its Cell-Cell and Cell Matrix Adhesion Functions, M. E. Hemler, M. J. Elices, C. Parker and Y. Takada, Immunological Reviews, 114 (1990) 45-65.] Integrin .alpha.4.beta.1 is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils. Unlike other .beta.1 integrins that are involved only in cell-extracellular matrix interactions. .alpha.4.beta.1 mediates both cell-cell and cell-extracellular matrix interactions. Cells expressing activated .alpha.4.beta.1 bind to the carboxy-terminal cell binding domain of fibronectin (non Arg-Gly-Asp mediated), to VCAM-1 expressed on endothelial cells, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF-.gamma., TNF-.alpha. and
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Celsa Bennett
Zeneca Limited
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