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Researchers pave the way to protein therapy in humans

St. Louis, Sept. 3, 1999--For decades, pharmaceutical companies have struggled to overcome the molecular equivalent of the Great Wall of China: the outer membrane of cells, which prevents all but the tiniest of proteins from entering. Now researchers have slipped a protein that's more than 200 times larger than the average drug into the cells of living mice and shown that the protein functions.

"For the very first time, we've introduced a large, biologically active protein into every cell of the body-- including cells in the brain that are normally protected by the blood-brain barrier," says Steven F. Dowdy, Ph.D., who led the research team at Washington University School of Medicine in St. Louis. The group published its results in today's issue of Science.

Dowdy is an assistant investigator of the Howard Hughes Medical Institute and an assistant professor of pathology and medicine. Steven R. Schwarze, Ph.D., a postdoctoral fellow in his laboratory, was lead author of the paper.

Getting full-sized, therapeutic proteins into cells would be advantageous because smaller drugs tend to interact with unintended targets. Larger proteins fit only onto the molecules for which they were designed, so they could be given in substantially lower doses, resulting in fewer side effects.

Dowdy led a previous research team that used test-tube experiments to smuggle an enzyme into HIV-infected cells. The results, reported in Nature Medicine last December and January focused on a human enzyme that makes cells self-destruct. The enzyme was modified to include a string of 11 amino acids that served as a passport for crossing a cell's outer membrane. But the researchers needed to prove that large proteins could slip into cells in model animals before considering human applications.

In the Science study, Dowdy and fellow investigators first attached a molecular passport known as a protein transduction domain (PTD) to
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Contact: Barbra Rodriguez
rodrigub@medicine.wustl.edu
314-286-0122
Washington University School of Medicine
3-Sep-1999


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