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PROTEIN FROM AFRICAN SNAKE INSPIRES DEVELOPMENT OF AGGRASTATÆ
Drug companies search the world for new sources of medicines and follow clues from nature to discover promising leads in the most unlikely places. The 10-year story behind the newest heart drug -- Merck's platelet blocker AggrastatÆ (tirofiban hydrochloride) -- begins with the deadly venom of an African snake and ends with a beneficial new medicine created in the laboratory.
This new heart drug, approved today (May 14) by the U.S. Food and Drug Administration, is evidence of the scientific paradigm of transforming toxins into treatments. Aggrastat results from years of research, including work on the anti-clotting effects of the poisonous venom of the Saw-scaled viper, a small, wide-eyed snake found in Africa.
A poisonous snakebite can leave its victim bleeding to death because some snake venom contains powerful proteins that keep blood from clotting. "We studied the venom of a dozen different vipers, and in each found proteins that prevent human blood platelets from sticking together to form potentially dangerous clots," says Robert Gould, Ph.D., executive director of pharmacology, Merck Research Laboratories, West Point, PA.
"We were most interested in the protein that we found in the venom of the Saw-scaled viper because the chemical sequence was simple, therefore more easily replicated in the lab," Gould says. "That the protein was so potent also made it easier to study." Gould and his Merck research team, along with researchers from Philadelphia's Temple University, isolated and synthesized the small protein, called echistatin, which naturally prevents platelets from sticking together.
The researchers then refined their understanding of the specific protein regions that play a direct role in preventing platelets from sticking together without being toxic to patients. This knowledge helped chemists synthesize Aggrastat, a medicine that is designed to block certain blood platelet receptors. Aggrastat itself is not snake venom, rather it is a small, organic molecule that was created to mimic a portion of the natural protein found in the viper venom.
Aggrastat was approved for intravenous use in combination with heparin for treatment of the acute coronary syndromes of unstable angina and non-Q-wave myocardial infarction, including patients who are to be managed medically and those undergoing angioplasty or atherectomy. Aggrastat works by blocking glycoprotein llb/llla receptors on the surface of blood platelets, thus preventing the sticky platelets from linking to each other and forming clots.
In clinical studies of nearly 7,300 patients, Aggrastat was generally well-tolerated. The most common side effect reported during therapy with Aggrastat when added to heparin or aspirin was bleeding. Because Aggrastat is a drug that affects the blood clotting system, it should not be used in patients who are at risk for bleeding complications.
Merck researchers have a long history of studying exotic animals as potential sources for new medicines, such as ticks for anticoagulant proteins and vampire bats for clot-busting proteins in their saliva. Today's research hero is the Saw-scaled viper.
Saw-scaled vipers, also known as "carpet" vipers, live in areas of sandy soil and rock outcroppings. They are native to Africa, India, and parts of the Middle East, and can be found in some U.S. zoos. These snakes are brownish or gray in color, patterned on the body with brownish blotches, a wavy white stripe, and a dark cross on their heads. When aroused, they coil and twist, rubbing their serrated scales against each other to create a sound similar to that of a saw cutting wood. Saw-scaled vipers are quick to strike, and their venom is highly toxic to humans.
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