Agonizing dimeric cell-surface receptors with a receptor binding moiety and chelating metal

• Main Authors: Luengo, Juan I, Miller, Stephen G, Gleason, John G
• Format: Patent
• Language: English
• Published: 02.07.2002

This invention relates to metal complexed receptor ligands, methods for making and identifying them and their use as agonist of dimeric receptors. More specifically, the invention describes a method to promote the oligomerization of dimeric receptors. Dimeric cell-surface receptors in a subject are agonized by administering a metal chelated dimeric cell-surface receptor ligand formed by chelating a receptor binding moiety with a metal ion such as zinc, or by co-administering the receptor binding moiety and the metal ion. The binding moiety is a small organic molecule having a molecular weight of from about 100 to about 850, and metal chelation may form a symmetrical multimer such as a dimer of the receptor binding moiety. An example is bis{2,5-bis[2-benzimidazolylimino]-3a,6a-bis(2-pyridyl)-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazole-N,N′}-zinc(II). Dimeric cell surface receptors include granulocyte colony-stimulating factor, erythropoeitin receptor, macrophage-colony-stimulating factor, growth hormone receptor, thrombopoietin receptor, interferon alpha receptor, interferon beta receptor, tyrosine kinase receptor, insulin receptor and leptin receptor. A pharmaceutical composition containing a carrier and the ligand or the binding moiety and the metal ion separately can be used to enhance leukocyte production and to treat bacterial and fungal infections.