November 2005

N.D. researchers study molecule that may lead to new treatments for diseases

By: William G. Gilroy

Much of the recent discussion about new treatments for disabling diseases has focused on the promise of stem cell research. However, a new therapeutic compound developed by a team of Notre Dame researchers is showing great promise as a means of preventing the cell injury and death associated with strokes and other neurodegenerative diseases.

Shahriar MobasheryShahriar Mobashery, a bioorganic chemist and Navari Family Chair in Life Sciences, and his colleagues have been studying the important role that inhibition of a class of enzymes called gelatinases plays in many diseases processes.

“There are 26 metalloproteinases (MMPs) in humans and over the last 10 years we have become convinced that two of these gelatinases, namely MMP-9 and MMP-2, are the most important for a number of diseases,” Mobashery said. “A decade ago, drug companies believed that gelatinase inhibitors showed great promise for treating diseases and began devoting considerable attention to them.”

The early promise failed to develop into positive results.

“These huge drug development programs rushed a set of broad-spectrum inhibitors for MMPs into clinic trials which failed, substantially setting back this field of research,” Mobashery said.

The cause of this failure was that the drugs developed attempted to inhibit the broad class of all 26 MMPs, rather than specifically targeting important MMPs. The resulting drugs had serious side effects in the body.

metalloproteinases (MMPs) research

Mobashery, however, remained convinced that gelatinase inhibition was a promising area of research and by 2000 had developed a new compound, named SB-3CT, which targeted and inhibited gelatinases selectively. SB-3CT acts only on MMP-2 and MMP-9 and as such is unique.

Mobashery worked in collaboration with Dr. Stuart Lipton of the Neuroscience and Aging Center at the Burnham Institute in La Jolla, Calif., to study the role SB-3CT might play in alleviating the consequences of stroke. Previous research at Burnham has shown that damage to the brain subsequent to stroke was due to the activity of MMP-9.

Stroke is one of the leading causes of death in the United States.

“A stroke cuts off blood supply to the brain, resulting in not enough oxygen to the tissue, a condition known as hypoxia,” Mobashery said. “The brain cells undergo a set of biochemical transformations resulting in cell death.”

There is but one medical treatment for stroke in the United States, “tPA,” or tissue plasminogen activator, which must be administered within three hours of a stroke to restore blood flow to the brain.

“Unfortunately, tPA is not an ideal treatment because it not only goes into the arteries and unclogs blood clots, but also induces an up shift in the quantity of MMP-9, which is harmful to the brain” Mobashery said.

In the study, Mobashery and the Burnham researchers discovered that SB-3CT protected against brain damage in mice undergoing a stroke, compared to mice that did not receive the compound. In SB-3CT-treated mice, MMP-9 activity dropped significantly. SB-3CT reduced brain damage to only 30 percent of that seen in control mice receiving a placebo, which is considered extremely significant.

Also, SB-3CT appeared to preserve neurological function and behavior in mice undergoing a stroke. Additionally, the study revealed that significant therapeutic action of SB-3CT was seen up to six hours after the initial damage.

While studies in mice are not always applicable to humans, Mobashery and the Burnham researchers believe that the study results offer great potential for SB-3CT as a gelatinase-specific inhibitor.

“SB-3CT can’t treat clots like tPA, but used in conjunction with it, it could preserve the action of tPA as a clot buster while eliminating a culprit that leads to brain death,” Mobashery said.

Mobashery, Mayland Chang, a colleague from Notre Dame, Rafael Fridman of Wayne State University, and Achim Kruger of the University of Munich revealed that SB-3CT has a significant anticancer property as well.

“Cancer is 90 percent fatal when it metastasizes, or spreads from one part of the body to another,” Mobashery said. “The way this happens is that cells from the tumor mass break off and travel to other organs where they recolonize. Gelatinases, especially MMP-9, play an important role in how the cell sheds and later implants itself in another organ.”

It has long been the consensus opinion of scientists that MMPs and, in particular, MMP-2 and MMP-9, play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in patients were disappointing. Mobashery again feels that a lack of inhibitor selectivity was the cause of the problem, as excessive activities of the inhibitors cause complications in the trials.

The recent contribution by the Notre Dame team and colleagues tested SB-3CT as an inhibitor of liver metastasis in an aggressive mouse model of T-cell lymphoma. Again, studies in mice do not always prove applicable to humans, but the researchers feel the study reveals great potential for the compound.

“Metastasis into the liver completely shuts down the liver and is 100 percent fatal, often within 10 to 11 days,” Mobashery said. “When the mice went on our compound, it dramatically reduced the rate of the metastasis. The life expectancy of the animals on the compound was prolonged 30 to 40 percent. Our approach to inhibitor design holds the promise of a novel potential recourse in anticancer therapy and deserves further exploration.”

Mobashery also suggests that the model may produce dramatic effects in prostate cancer that metastasizes to the bones and in other diseases, such as arthritis and inflammation-based diseases that increasingly afflict Americans.

Contact Shahriar Mobashery at mobashery.1@nd.edu

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