Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1997-10-31
2000-11-21
Ulm, John
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 71, 4352523, 4353201, 530350, 536 235, C07K 14705, C12N 1512
Patent
active
061501328
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to chemokine receptors.
Chemokines are a growing family of chemotactic cytokines, which have been implicated to play a role in the recruitment and activation of cells (Oppenheim, J. J. et al., Ann Rev Immunol., 9 617-48, (1991), Schall, T. J., Cytokine, 3 165-183, (1991)). They are primarily responsible for the activation and recruitment of leukocytes, but not exclusively so. Further analysis of this superfamily of proteins has shown that it can be divided up into two further subfamilies of proteins. These have been termed CXC or .alpha.-chemokines, and the CC or .beta.-chemokines based on the spacings of two conserved cysteine residues near to the amino terminus of the proteins.
To date two receptors have been identified for the CC chemokine family. The first, which is receptor primarily for MIP-1.alpha. (Macrophage inflammatory polypeptide-1.alpha.) and RANTES (Raised on Activation, Normal T-cell derived and Secreted) has been described previously (Gao, J. L. et al., J. Exp. Med., 177 1421-7 (1993), Neote, K. et al., Cell 72 415-25 (1993)). The second CC-chemokine receptor which has been recently described is for MCP-1 (monocyte chemotractant protein-1) Charo I. et al., Proc. Natl. Acad. Sci. USA 91 2752-2756 (1994). More recently, another receptor US28, expressed by the human cytomegalovirus, has been shown to be a receptor for RANTES, MIP-1.alpha., and MCP-1 (Gao, J. L. and Murphy P. M., J. Biol. Chem. 269, 28539-28542 (1994)). All three receptors are of the seven transmembrane alpha helical segment type, and are expressed into the membranes of cells.
However there remains a need to identify hitherto undisclosed chemokine receptors and to characterise them in order to develop a more complete picture of the structure and function of chemokine receptors.
According to the present invention there is provided a chemokine receptor having the amino acid sequence shown in FIG. 3.
This receptor is preferably capable of binding MCP-1, MIP-1.alpha. and RANTES. It may be important in basophil and T-cell function.
It can be used to screen for pharmaceutically active agents. The present invention therefore includes within its scope such agents (which may or may not be proteins). They may be provided in a pharmaceutical composition together with a pharmaceutically acceptable carrier.
Such a composition is within the scope of the present invention. It may be prepared by admixing the carrier with the pharmaceutically active agent under sterile conditions. The pharmaceutical composition may be provided in unit dosage form. It may be present as part of a kit including instructions for use.
The pharmaceutical composition may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
A receptor of the present invention can be used to screen for agents useful in treating allergies e.g. asthma, atopic dermatitis, rhinitis, hay fever, eczema or food allergies. It may also be useful in screening for agents useful in treating conjunctivitis. MCP-1, MIP-1.alpha. and RANTES all bind to the receptor of the present invention and are capable of causing histamine release from basophils. An agent which blocks this binding may thereby prevent or reduce the release of histamine from basophils (i.e. act antagonistically to MCP-1, MIP-1.alpha. or RANTES). Such agents may be variants of MCP-1, MIP-1.alpha. or RANTES (in which one or more amino acids are deleted, substituted or inserted relative to MCP-1, MIP-1.alpha. or RANTES), although this is not essential.
It may also be involved in the activation of T-lymphocytes, a common characteristic of immune and other inflammatory states.
The binding of agents to the receptor of the present invention can be assayed by suitable techniques.
For example, electrophysiological techniques may be used. In one such technique, a Xenopus oocyte, for example,
REFERENCES:
Gieorge et al. Macromolecular Sequencing and Synthesis. Alan R. Liss, Inc. pp. 127-149, 1988.
Neote et al. Molecular Cloning, Functional Expression, and Signaling Characteristics of a C-C Chemokine Receptor. Cell 72:415-425, Feb. 1993.
Charo, Israel F. et al., "Molecular Cloning and Functional Expression of Two Monocyte . . . ", Proc. Natl. Acad. Sci. USA, vol. 91, Cell Biology, Mar. 1994, pp. 2752-2756.
Gao, Ji-Liang et al., "Structure and Functional Expression of the Human . . . ", Journal of Experimental Medicine, vol. 177, May 1993, pp. 1421-1427.
Gao, Ji-Liang et al., "Human Cytomegalovirus Open Reading Frame US28 . . . ", Journal of Biological Chemistry, vol. 269, No. 46, Nov. 18, 1994, pp. 28539-28542.
Graham, G. J. et al., "Identification and Characterization of an Inhibitor . . . ", Nature, vol. 344, Mar. 29, 1990, pp. 442-444.
Power Christine A.
Wells Timothy N. C.
Glaxo Group Limited
Ulm John
LandOfFree
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