Chemokine analogs for the treatment of human disease

Patent Number: 7,091,310

This patent is useful for stem cell mobilization, stem cell homing, as well as a variety of other applications involving various chemokines. Specifically, the invention covers peptides that antagonize or agonize receptors for IL-8, IP-10, MIP-1 alpha., MCP-1, RANTES, I-309, and CCL28. IL-8 is known to be associated with inflammation and in terms of stem cells is known to be associated with stem cell mobilization after myocardial infarction (Schomig K et al. Interleukin-8 is associated with circulating CD133+ progenitor cells in acute myocardial infarction. Eur Heart J. 2006 May;27(9):1032-7). IP-10 inhibits proliferation of hematopoietic stem cells (Sarris AH et al. Human interferon-inducible protein 10: expression and purification of recombinant protein demonstrate inhibition of early human hematopoietic progenitors. J Exp Med. 1993 Sep 1;178(3):1127-32) but also is associated with causing chemoattraction of GM-CSF treated CD34 stem cells through the receptor CXCR-3 (Jinquan T et al. CXCR3 expression on CD34 hemopoietic progenitors induced by granulocyte-macrophage colony-stimulating factor: II. Signaling pathways involved. J Immunol. 2001 Oct 15;167(8):4405-13.). MIP-1 alpha is also an inflammatory chemokine, it is known to inhibit proliferation of early hematopoietic progenitor stem cells (Ottersbach K et al. Macrophage inflammatory protein-1alpha uses a novel receptor for primitive hemopoietic cell inhibition. Blood. 2001 Dec 1;98(12):3476-8.). MCP-1 is a chemoattractant not only for bone marrow progenitors when inducing repair of endothelium (Fujiyama S et al. Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res. 2003 Nov 14;93(10):980-9) But also for neuronal progenitor stem cells ( Belmadani A et al. Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. J Neurosci. 2006 Mar 22;26(12):3182-91). RANTES is an inflammatory derived chemokine, whose stem cell modulating function is relatively unknown. I-309 (CCL-1 or CCR8 agonist) is another chemokine whose stem cell role is unclear at present. However it is a potent chemoattractant of T regulatory cells (Freeman CM et al. CCR8 is expressed by antigen-elicited, IL-10-producing CD4+CD25+ T cells, which regulate Th2-mediated granuloma formation in mice. J Immunol. 2005 Feb 15;174(4):1962-70). CCL-28 is the ligand of CCR-10 and is associated with chemotaxis of T regulatory cells (Eksteen B et al. Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10. J Immunol. 2006 Jul 1;177(1):593-603.). The patent covers composition of matter, method of production, method of activating a receptor, method of inducing calcium flux, and a compound containing the composition of matters described.

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