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Scientists Show that Small Molecules Can Mimic Protein Hormones, Elucidate the Structure of an Activated Receptor Complex

July 25, 1996, La Jolla, CA. -- In a collaborative effort between laboratories at The Scripps Research Institute (TSRI), R.W. Johnson Pharmaceutical Research Institute, (Raritan, N.J.) and Affymax Research Institute (Palo Alto, CA.), researchers have, for the first time, provided evidence that small peptides can mimic large protein hormones. The scientists not only identified a peptide that binds to and activates the receptor for erythropoietin (EPO) -- a hormone that controls red blood cell production by stimulating the differentiation of erythroid progenitor cells in the bone marrow -- but found that it binds to a similar site as the natural hormone, EPO.

Using a method known as x-ray crystallography, the TSRI scientists have determined the structure of one of these peptides with the EPO receptor, thereby contributing to an understanding of why it functions as an agonist.

Further, in the companion paper by Wrighton et al, researchers at Johnson & Johnson and Affymax have shown that the peptide activates the EPO receptor in a variety of cell-based and animal assays.

The studies have implications for the production and method of administration of erythropoietin, the largest single product in biotechnology whose recombinant form is widely used in the treatment of patients with anemia caused by renal failure, cancer chemotherapy and AZT treatment. Currently available by injection only, this work may contribute to the possibility of designing orally active drugs that could promote the growth of red blood cells.

According to TSRI President, Richard A. Lerner, M.D., "This stunning result is a validation of the power of combinatorial chemistry methodology coupled with x-ray structure studies to provide a rational basis for innovative drug design."

The work is published in this week's issue of Science in an article entitled, "Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 Å," by Drs. Oded Livnah, Enrico A. Stura, Dana L. Johnson, Steven A. Middleton, Linda S. Mulcahy, Nicholas C. Wrighton, William J. Dower, Linda K. Jolliffe, and Ian A. Wilson.

The work by TSRI scientists was funded by Johnson & Johnson; the Skaggs Institute for Research; and the National Institutes of Health (which contributed approximately 40% of the funding).

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