Nephrology Dialysis Transplantation, Vol 14, Issue 90002 80-84, Copyright © 1999 by Oxford University Press
F Barbone, D Johnson, F Farrell, A Collins, S Middleton, F McMahon, J Tullai and L Jolliffe
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.
Keywords: EPO mimetic peptide; haematopoietic cell
phosphatase
ORIGINAL ARTICLES
Plenary lecture. New epoetin molecules and novel therapeutic approaches
The R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Research, 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA; Corresponding author
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