New epoetin molecules and novel therapeutic approaches.
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.
Barbone
F P
FP
The R.W. Johnson Pharmaceutical Research Institute, Drug Discovery Research, Raritan, NJ 08869, USA.
Johnson
D L
DL
Farrell
F X
FX
Collins
A
A
Middleton
S A
SA
McMahon
F J
FJ
Tullai
J
J
Jolliffe
L K
LK
D000595:Amino Acid Sequence; D000818:Animals; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000627:therapeutic use; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D017467:Receptors, Erythropoietin / Q000378:metabolism
C099963:EPO mimetic peptide 1; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases