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Research from UTHSC, Dartmouth
Natural anti-bacterial agent has potential to cure heart disease

San Antonio (Sept. 8, 2003) — When physicians and physiologists at Dartmouth Medical School injected mice with PR39, a natural anti-bacterial agent found in animals, they noticed, besides its predicted anti-inflammatory effects, an ability to induce formation of new blood vessels. Searching for an explanation of this rather unexpected property, they found that a cellular machine called the proteasome was involved. Then they turned to biochemists at The University of Texas Health Science Center at San Antonio (UTHSC) to define exactly what happened to the proteasome.

"They found us for two reasons. First, we have a quite unique technique to study structure of the proteasome and other large proteins," said Maria Gaczynska, Ph.D., assistant professor in the department of molecular medicine at UTHSC. "The technique is called atomic force microscopy. It allows researchers to directly observe, almost like in a living organism, how the surface of the proteasome responds to treatment with a drug molecule. We may be the only laboratory in the world that studies the proteasome in this manner. Second, we study proteasome regulation on a biochemical level, so it was natural for them to call us to see if we were interested in collaborating."

The resulting research, published in the July issue of Biochemistry, reveals a new understanding of vital cellular functions controlled by the proteasome and opens a potentially novel avenue for the development of medications to treat diseases from cancer to heart attacks. "It (PR39) is not something you will give patients now, obviously, but it represents a new concept in the rational design of novel drugs," said Dr. Gaczynska, who performed the biochemical work at UTHSC's Institute of Biotechnology with postdoctoral fellow Pawel Osmulski, Ph.D.

"The proteasome is a very precise machine inside the cell," Dr. Gaczynska said. "It not only digests some proteins to destroy them, but activates others in a tightly regulated manner. Atomic force microscopy studies showed that PR39 is like a single nut on a bolt in this machine. Loosening or tightening the nut can change the performance of the machine. What's exciting about this is the finding that altering the proteasome with PR39 does not shut down the machine completely, because the proteasome has numerous vital functions that must not be interrupted."

PR39 inhibited the proteasome's destruction of only two proteins — one that fights inflammation and another that promotes growth of new blood vessels. This fit perfectly with the earlier observation.

Learning to alter just a few functions might lead to proteasome-related therapies, such as preferential killing of cancer cells while leaving healthy cells intact or selective growth of blood vessels as an effective answer to advanced heart disease. "It is possible that compounds similar to PR39 will be useful as drugs," Dr. Gaczynska said. "At this moment, it is too early to predict if this exact compound could be used."

For many years, PR39 was known to fight infection in wounds by killing bacteria. "Its ability to affect the proteasome came as a big surprise for us," Dr. Gaczynska said. "It works with surgical precision. We are aggressively pursuing this lead in the hope and expectation of developing better treatments for heart disease, in particular."

Contact: Will Sansom