SELECTION OF SMALL MOLECULE MIMETICS OF ERYTHROPOIETIN

促红细胞生成素受体(EPOR)是一种跨膜蛋白，它介导从激素促红细胞生成素(EPO)到血细胞保护剂的信号传递，该信号诱导细胞成熟为红细胞。像许多跨膜受体蛋白一样，EPOR在EPO蛋白的二价结合反应中通过二聚体将信号传递到细胞膜上。一种小的有机分子可以在没有EPO的情况下使EPOR二聚化，作为严重贫血患者的治疗方法将具有很高的价值。一种小肽EPOR模拟物已经被开发出来，它可以使EPOR二聚化，尽管基于多肽的药物存在生物利用度低和在体内快速崩解的问题。NeoGenesis已经开发了一个基于组合化学的药物发现计划，该计划能够合成和快速筛选数百万个类药物分子，以识别任何蛋白质靶标的小分子配体。该项目建议合成新的有机小分子组合文库，并开发新的筛选方案，以识别可二聚化或可修饰为人EPOR二聚化的化合物。如果这一策略成功，它将应用于其他以类似机制发挥作用的高价值药物靶标，例如生长激素和胰岛素的受体。建议的商业应用：该项目将开发一种促红细胞生成素的小分子模拟物，这里开发的技术将适用于生长激素、胰岛素和其他激素的小分子模拟物的开发，这些激素通过跨膜受体的二聚化发挥作用。

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. PROPOSED COMMERCIAL APPLICATIONS: 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.