Barbone F P, Johnson D L, Farrell F X, Collins A, Middleton S A, McMahon F J, Tullai J, Jolliffe L K
The R.W. Johnson Pharmaceutical Research Institute, Drug Discovery Research, Raritan, NJ 08869, USA.
Nephrol Dial Transplant. 1999;14 Suppl 2:80-4. doi: 10.1093/ndt/14.suppl_2.80.
Erythropoietin (EPO) is a 34 kDa protein that is the primary regulator of red blood cell production. EPO facilitates its effect by binding to the cell surface EPO receptor which initiates the JAK-STAT signal transduction cascade. The search for small mimetic molecules of EPO has led to the discovery of a family of peptides that demonstrate EPO mimetic activity. A member of this peptide family, EMP1 (EPO mimetic peptide 1), was used to solve the crystal structure of the soluble EPO receptor in complex with this peptide. The structure revealed a 2:2 stoichiometry of receptor to peptide, with each peptide contacting both receptor molecules in a symmetrical fashion. The potency of the EMPs could be improved through the covalent dimerization of two peptide molecules. Further investigations of EMP EPO receptor complex structures revealed the formation of a non-productive receptor dimer using an inactive peptide. An alternative approach towards the identification of an EPO-like mimetic is to target an intracellular signalling molecule such as haematopoietic cell phosphatase (HCP), also known as SHP1. Inhibiting HCP causes responsive cells to be hypersensitive to EPO. The cloned HCP protein has been utilized in screening assays to identify small molecule inhibitors of HCP.
促红细胞生成素（EPO）是一种34 kDa的蛋白质，是红细胞生成的主要调节因子。EPO通过与细胞表面的EPO受体结合来发挥作用，该受体启动JAK-STAT信号转导级联反应。对EPO小分子模拟物的研究导致发现了一类具有EPO模拟活性的肽。该肽家族的一个成员EMP1（EPO模拟肽1）被用于解析可溶性EPO受体与该肽形成的复合物的晶体结构。该结构显示受体与肽的化学计量比为2:2，每个肽以对称方式与两个受体分子接触。通过两个肽分子的共价二聚化可以提高EMPs的效力。对EMP-EPO受体复合物结构的进一步研究揭示了使用无活性肽形成非生产性受体二聚体的情况。另一种鉴定EPO样模拟物的方法是靶向细胞内信号分子，如造血细胞磷酸酶（HCP），也称为SHP1。抑制HCP会使反应性细胞对EPO高度敏感。克隆的HCP蛋白已用于筛选试验，以鉴定HCP的小分子抑制剂。
