Compound that could lead to new blood pressure drugs discovered

 
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Washington, May 2 : Researchers at the University of Florida have identified a drug compound that could dramatically lower blood pressure, improve heart function and prevent damage to the heart and kidneys in people with persistent hypertension.

According to researchers, the findings could lead to a new class of antihypertensive drugs designed to address two major problems linked to cardiovascular disease: high blood pressure and the tissue damage associated with it, known as fibrosis.

"When people have heart attacks (or suffer from hypertension) the blood vessels get more rigid. We discovered a compound that reverses the fibrosis that makes the blood vessels more rigid," said study author David Ostrov, Ph.D., an assistant professor in the UF College of Medicine's department of pathology, immunology and laboratory medicine.

Angiotensin-converting enzyme plays a significant role in the development of high blood pressure.

It produces angiotensin II, a potent hormone that triggers the condition and boosts the development of cardiovascular disease by constricting blood vessels, causing blood pressure to rise.

People therefore take ACE inhibitors but these drugs have limited capacity to repair heart function and to reverse tissue damage.

On contrary, the enzyme ACE2 not only lowers levels of angiotensin II but also converts it to a hormone that helps protect the cardiovascular system.

"Only recently has it come to be appreciated that ACE and ACE2 play a very important role in balancing the activity of the other one to maintain normal blood pressure. They work in harmony," Ostrov said.

Assuming that activating ACE2 could be beneficial, researchers set out to discover a compound that enhances the enzyme's activity.

They used one of the world's most powerful supercomputers to process 140,000 prospective drug compounds in a matter of weeks.

The computer predicted which molecules would be most likely to enhance the activity of ACE2, rotating them in thousands of different orientations to see how they would bind to certain pockets on the enzyme's surface.

"This project had a very small likelihood of succeeding because it's much easier to inhibit activity rather than to enhance it," Ostrov said.

"If you consider the structure of an enzyme's active site it's easy to see that if you plug up the active site it's not going to work. But how can one make the enzyme actually work better, this seemed to be a very significant challenge we were probably not likely to overcome. We tried anyway and it worked.

"That in itself is a significant accomplishment because no one has ever specifically identified a compound that enhances the activity of an enzyme using a rational structure-based approach," he added.

Researchers said that the enzyme exists in two forms: like a Pac-Man with a mouth that has chomped closed, and like a Pac-Man with a mouth that remains wide open. The molecule that worked best fit in a structural pocket in the enzyme's open conformation.

"So in other words, stabilizing the open conformation may be the reason why we enhance the activity of the enzyme," he said.

After hitting on the 'lead' compound, researchers tested it in hypertensive rats that had developed fibrosis of the heart and kidney. The animals received the drug for two weeks.

Ostrov found that the tissue samples from treated animals revealed a significant decrease in fibrosis of the heart, kidney and blood vessels.

The study appears in an edition of the American Heart Association journal Hypertension.

ANI
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