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Science 26 July 1996:
Vol. 273. no. 5274, pp. 458 - 463
DOI: 10.1126/science.273.5274.458
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Research Articles

Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin

Nicholas C. Wrighton, * Francis X. Farrell, Ray Chang, Arun K. Kashyap, Francis P. Barbone, Linda S. Mulcahy, Dana L. Johnson, Ronald W. Barrett, Linda K. Jolliffe, William J. Dower

Random phage display peptide libraries and affinity selective methods were used to isolate small peptides that bind to and activate the receptor for the cytokine erythropoietin (EPO). In a panel of in vitro biological assays, the peptides act as full agonists and they can also stimulate erythropoiesis in mice. These agonists are represented by a 14- amino acid disulfide-bonded, cyclic peptide with the minimum consensus sequence YXCXXGPXTWXCXP, where X represents positions allowing occupation by several amino acids. The amino acid sequences of these peptides are not found in the primary sequence of EPO. The signaling pathways activated by these peptides appear to be identical to those induced by the natural ligand. This discovery may form the basis for the design of small molecule mimetics of EPO.

N. C. Wrighton, R. Chang, A. K. Kashyap, R. W. Barrett, and W. J. Dower are with Affymax Research Institute, 4001 Miranda Avenue, Palo Alto, CA 94304, USA. F. X. Farrell, F. P. Barbone, L. S. Mulcahy, D. L. Johnson, and L. K. Jolliffe are in the Department of Drug Discovery Research, R. W. Johnson Pharmaceutical Research Institute, 1000 Route 202, Raritan, NJ 08869, USA.
*   To whom correspondence should be addressed.


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The Structural and Functional Basis of Cytokine Receptor Activation: Lessons From the Common beta  Subunit of the Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-3 (IL-3), and IL-5 Receptors.
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Blood 89, 1471-1482
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Activating Mutations in Cytokine Receptors: Implications for Receptor Function and Role in Disease.
T. J. Gonda and R. J. D'Andrea (1997)
Blood 89, 355-369
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Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif.
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J. Biol. Chem. 275, 23783-23789
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The Role of the Hinge Region of the Luteinizing Hormone Receptor in Hormone Interaction and Signal Generation.
H. Zeng, T. Phang, Y. S. Song, I. Ji, and T. H. Ji (2001)
J. Biol. Chem. 276, 3451-3458
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