Molecular Finding Could Enhance Drug Development

Research targets protein receptors that transmit signals through cell membranes

Edward Edelson

Edward Edelson

Updated on August 04, 2006

THURSDAY, April 20, 2006 (HealthDay News) -- Researchers say they may have opened the way to a new generation of more effective drugs by unlocking a complex signaling system inside human cells.

The researchers at the University of Rochester Medical Center in New York said they've delved to the core of what are called G-protein coupled receptors, which are complex molecules that transmit signals through cell membranes. These GPCRs are the targets of 12 of the best-selling drugs for conditions including heart failure, high blood pressure, breast cancer and schizophrenia, the scientists said.

The drugs attach themselves to the outer portion of the receptors, setting off a molecular sequence that eventually results in the release of molecules designated G proteins, which give the system its name. A G protein then breaks up to release what is called a gamma-beta subunit. It is this subunit that turns on enzymes to perform specific actions, for example, sending a signal to immune system cells to attack an invading virus or sending a signal to heart cells to control heart rhythm.

What the Rochester researchers did was first to identify one location on the gamma-beta subunit where most of the interaction with enzymes takes place, then determine the molecular structure of that "hot spot." Then they looked for molecules that bind to specific parts of the hot spot.

Using a database of molecules maintained by the National Cancer Institute, "we found about 20 such molecules," said study leader Alan V. Smrcka, an associate professor of pharmacology, physiology, oncology, biochemistry and biophysics at Rochester.

Tests of one molecule showed that it increased the painkilling ability of morphine elevenfold, Smrcka said. Tests of another showed that it reduced the activation of enzymes that cause inflammation.

"We think we could alter the potency and specificity of many existing drugs," Smrcka said. "We are refining our techniques for finding these molecules and investigating their role in conditions such as heart failure and pain relief and inflammation."

Any molecule to control gamma-beta subunit activity for medical purposes would have to be small enough to pass through the cell membrane, he said. Such molecules would probably be given in combination with medications to increase their effectiveness, Smrcka said.

The findings appear in the April 21 issue of Science.

Dr. Richard Neubig, a professor of pharmacology at the University of Michigan, said he thought the new research is "very important."

"It does two things," he said. "It shows that it is possible to target protein-protein interactions in cells, but more than that it brings incredible subtlety to that protein target."

By tinkering with molecules that bind to the hot spot, Neubig said, it may be possible to find some that have "many possible actions on one target."

Elliott Ross, a professor of pharmacology at the University of Texas Southwestern Medical Center at Dallas, who has worked with Smrcka, was more cautious.

"From a G-protein point of view, it is obviously very interesting," he said. "But it is a long way from a drug, obviously."

While the molecule used by the Rochester researchers did alter the effect of morphine, it's not yet certain that it did so by binding to the hot spot, Ross said. Other researchers have used similar methods to screen for molecules that bind to a specific site, have found what they were looking for "and found subsequently that they bind somewhere else," he said.

Still, "this is not a common kind of observation, and that's what makes it striking," Ross said.

Smrcka said some pharmaceutical companies have expressed interest in the work "and have given us a little money to explore with. Some are interested in pain relief, others in inflammation, others in heart failure."

More information

More detail about g-protein coupled receptors is offered by the National Institute of Diabetes and Digestive and Kidney Diseases.

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