SELECTION OF SMALL MOLECULE MIMETICS OF ERYTHROPOIETIN

促红细胞生成素受体（EPOR）是一种跨膜蛋白，介导从促红细胞生成素激素（EPO）到血细胞蛋白的信号传递；这个信号诱导细胞成熟为红细胞。像许多跨膜受体蛋白一样，EPOR通过二聚体反应EPO蛋白的二价结合，在细胞膜上传递信号。在缺乏EPO的情况下，一种可以使EPOR二聚的小有机分子将被高度评价为治疗严重贫血患者的一种治疗方法。一种小肽EPOR模拟物已经被开发出来，它可以使EPOR二聚体，尽管是肽。基于药物的生物利用度差，体内分解快。NeoGenesis开发了一个基于组合化学的药物发现项目，该项目能够合成并快速筛选数百万种药物样分子，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，以确定二聚化或可以修饰为二聚化人EPOR的化合物。如果这个策略是成功的，它将被应用到其他高价值的药物靶点，通过类似的机制工作，如生长激素和胰岛素的受体。拟议的商业应用：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、胰岛素和其他通过跨膜受体二聚化起作用的激素的小分子模拟物的开发。

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.