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Cell Insight May Lead to New Drug Targets

Agents against Alzheimer's, Parkinson's, diabetes are possible, researchers say

THURSDAY, Feb. 10, 2005 (HealthDay News) -- After combing through thousands of candidates, researchers say they've identified a compound that can protect, in a whole new way, cells threatened by disease.

The breakthrough may pave the way to drugs that fight illnesses such as Alzheimer's, Parkinson's disease, diabetes and a host of viral infections, the scientists said.

"That's why there's so much interest in this paper," said lead researcher Junying Yuan, a professor of cell biology at Harvard University Medical School.

Her team's findings are published in the Feb. 11 issue of Science.

Almost every illness involves the death of an excessive number of body cells due to stresses from both inside and outside the cell. Biologists call one of the most potent forms of cellular stress "endoplasmic reticulum (ER) stress."

"The endoplasmic reticulum is a tiny organ near the cell's nucleus," Yuan explained. "It's responsible for making proteins that are then exported up to the outside of the cell."

In neurodegenerative diseases such as Alzheimer's, Parkinson's and Lou Gehrig's disease, as well as in other illnesses, outside pressures can cause this cellular organ to malfunction.

"It's very sensitive to stress, which affects its ability to fold the proteins -- they need to be folded a certain way for transport," Yuan said. When this misfolding occurs, proteins start "backing up" in the endoplasmic reticulum, "like a room getting full of junk," she said.

"There's increasing thought, in a number of places, that neurodegenerative diseases are, at their foundation, diseases of protein folding," added Bill Thies, vice president for medical and scientific affairs at the Alzheimer's Association. Finding ways to stop the misfolding of proteins in cells "could be broadly applied to a lot of these diseases, including Alzheimer's, Parkinson's disease, ALS [Lou Gehrig's disease], and others," he said.

For decades, cell biologists and medical researchers have looked for ways to protect cells from ER stress caused by disease. One way is through drugs that inhibit kinases -- cellular compounds that add phosphates to proteins, a necessary step in the transport process.

But kinases have their opposite -- phosphatases, which go to work stripping phosphate from these proteins.

Interrupting either kinase or phosphatase activity stops the steady transport of proteins, giving clogged endoplasmic reticulums a bit of "breathing room."

"The 'junk' stops building up," Yuan explained. "So, inhibiting these processes can really protect cells."

Because there are hundreds of different kinases, "it's been relatively easy to make compounds to inhibit any one of them," Yuan said.

But finding a phosphatase inhibitor has proven a lot harder.

"That's because our genome only makes five or six kinds of phosphatases," Yuan said. "So, the problem has been to control the specificity -- how do we control that this particular phosphate is stripped off a protein, but not that one?"

Her team believes it has found the first such compound to do so -- a small molecule they called salubrinal. After looking through 19,000 candidate compounds, the researchers report that salubrinal appears to target only one specific cellular phosphotase complex.

"In essence, we've now shown, for the first time, that the phosphatase side of this process can now be inhibited by pharmaceuticals, just like kinases," Yuan said. "It's a whole new drug target -- not just this phosphatase, but the whole slew of phosphatase complexes may now be able to be inhibited."

Thies cautioned that, while promising, the Harvard advance must now make the leap from the Petri dish to animal models. "We should temper our enthusiasm with the recognition that this is a tissue-culture study, and tissue-culture is still a million miles away from coming up with an effective therapeutic," he said. "Whether a simple experiment, such as injecting this compound into a live animal is going to be compatible with [lab results], that's a good question."

But Yuan remains optimistic, describing the identification of salubrinal as an important first step in the search for new weapons against disease.

"Now that we have salubrinal as a tool, we can apply it to cells and see what it alters, chemically," she said. "Then, we can dissect out even more specific, downstream effects [to find targets] that may be even more effective."

More information

For more on the biology of Alzheimer's, head to the Alzheimer's Association.

SOURCES: Junying Yuan, professor, department of cell biology, Harvard Medical School, Boston; Bill Thies, vice president, medical and scientific affairs, Alzheimer's Association, Chicago; Feb. 11, 2005, Science
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