New epoetin molecules and novel therapeutic approaches

Erythropoietin (EPO) is a 34 kDa protein that is the primary regulator of r ed blood cell production. EPO facilitates its effect by binding to the cell surface EPO receptor which initiates the JAK-STAT signal transduction casc ade. 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 c rystal structure of the soluble EPO receptor in complex with this peptide. The structure revealed a 2:2 stoichiometry of receptor to peptide, with eac h 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 s tructures revealed the formation of a non-productive receptor dimer using a n inactive peptide. An alternative approach towards the identification of a n EPO-like mimetic is to target an intracellular signalling molecule such a s 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 inhibitor s of HCP.