The erythropoietin receptor (EPOR) is a transmembrane protein that mediates the transmission of a signal from the hormone erythropoietin (EPO) to a blood cell protenitor; this signal induces the maturation of the cell to an erythrocyte. Like many transmebrane receptor proteins, EPOR transmits the signal across the cell membrane by dimerizing in response to divalent binding by the EPO protein. A small organic molecule that can dimerize EPOR in the absence of EPO would be highly valued as a therapeutic treatment for severely anemic patients. A small-petide EPOR mimetic has been developed that can dimerize EPOR, although peptide.based drugs suffer from poor bioavailability and rapid breakdown in vivo. A combinatorial chemistry-based drug discovery program has been developed at NeoGenesis that is capable of synthesizing and rapidly screening millions of drug-like molecules to identify small-molecule ligands for any protein target. This project proposes the synthesis of new combinatorial libraries of small organic molecules and the development of novel screening protocols which will identify compounds that dimerize or can be modified to dimerize human EPOR. If this strategy is successful, it will be applied to other high-value drug targets which work by similar mechanisms, such as the receptors for growth hormone and insulin.
This project will develop a small-molecule mimetic of erythropoietin, and the technology developed here will be applicable to the development of small-molecule mimetics of growth hormone, insulin, and other hormones that function through dimerization of membrane-spanning receptors.
