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Snake venom is key ingredient in experimental drug for heart patients

Posted June 8

An experimental antiplatelet drug has surprising bite. Based on a protein found in snake venom, the new drug prevented blood clotting in mice without causing excessive bleeding after an injury, according to research published Thursday in the journal Arteriosclerosis, Thrombosis and Vascular Biology. The drug has yet to be tested in humans.

Bleeding is a common side effect in the current crop of available antiplatelet drugs, which are usually prescribed for heart patients to prevent blood cells, called platelets, from clumping together and forming clots. Depending on where they occur, clots can lead to a stroke or heart attack.

"As a scientist, it is always intriguing to learn from our mother nature," wrote Y. Jane Tseng, co-lead author of the study and a professor at the Genomics Center School of Pharmacy at National Taiwan University, in an email.

"There is a long history of using snake venom as a tool to study blood clotting mechanism," Tseng said, adding that the only available antiplatelet drugs used for thrombosis -- in which a clot occurs in a blood vessel and obstructs circulation -- are also based on venom, though not the same one used in her study.

Tur-Fu Huang, co-lead author of the study and a professor at the Graduate Institute of Pharmacology at National Taiwan University, said some snake venoms are neurotoxic -- poisonous to the brain -- while others are hemorrhagic and "affect blood coagulation and platelet function profoundly." The new research concentrated on venom that is hemorrhagic in nature.

In earlier work, Huang, Tseng and their colleagues found that trowaglerix from the venom of Tropidolaemus wagleri, commonly known as Wagler's pit viper, latched onto glycoprotein VI, a protein that sits on the surface of platelets.

"Not every snake venom acts in similar mode on platelets," Tseng said.

This attachment to glycoprotein VI is how trowaglerix stimulates platelets to form blood clots, the researchers learned. Platelets that are missing glycoprotein VI do not form blood clots and do not lead to severe bleeding.

If glycoprotein VI could be blocked, the research team hypothesized, would that prevent prolonged bleeding?

Putting this theory to the test, the researchers designed a molecule that could prevent clotting, and with added properties of trowaglerix, it did not cause severe bleeding. When this experimental drug was given to mice, the rodents showed slower blood clot formation, yet they also did not bleed longer than untreated mice, Tseng and her colleagues found.

"We successfully transformed trowaglerix into an anti-thrombotic agent," said Huang, who noted that the experimental drug was both effective and safe. Still, it needs further testing in animals and humans, which will take some time.

In the meantime, he said, it can be modified and optimized "to a more potent and stable agent" with potential for use in patients. Ultimately, he and his colleagues hope their work could yield an entire class of effective antiplatelet drugs with limited side effects.

'Of course there are safety issues'

Dr. Leslie Boyer, director of the VIPER Institute in Tucson, Arizona, said the new study "doesn't automatically mean that you have a drug, because of course there are safety issues."

"If they could find a very perfectly tuned molecule that a snake makes and give just the right dose," Boyer said, it might be "of therapeutic benefit to certain people."

"Venom contains many, many toxins. Even a single snake might have a 100 different types of venom molecules in their repertoire," said Boyer, who was not involved in the new study. She added that even though the modest dose of venom delivered when a snake bites is "quite toxic." But if you took that same poisonous venom, teased out the ingredients, scaled them down and used only a low dose, there are a lot of ingredients "that could be put to good use."

Toxicologists don't really distinguish one molecule as poisonous and another as benign, she said.

"It's all a matter of dose," Boyer said. "So a small dose of something might be a medicine, and a large dose becomes a poison."

Snakes have venom for all kinds of reasons, she said, though the biggest reason, perhaps, is "to make lunch hold still."

"A lot of snakes are relatively slow-moving creatures. They're ambush predators or they only travel a short distance to get their prey," Boyer said, noting that snakes "have one chance, one quick strike, to administer something that's going to make very fast-moving prey, like a bird or a rodent, hold still -- fall down and wait to be eaten."

The molecules in snake venom, then, interact with the nervous system or with the cardiovascular system and represent "potential drugs" that might act on the nervous system to lessen pain or relax muscles, she said. The venom molecules that interact with the cardiovascular system, as Tseng, Huang and their co-authors show, "have the potential to be used for blood pressure problems or for heart rate situations, things like that," Boyer said.

There are other toxins that have a direct effect on the tissues next to where the fang goes in that can digest proteins, which along with fat is what animals are made of, so "those molecules have all kinds of potential also," she said. "For instance, breaking down specific proteins is something that might be useful not only for drugs but maybe for laundry detergent or things that remove stains. Maybe they're good for recycling."

But, caution is required, Boyer said: The reason we know anything about venom at all is that snake bites make people sick.

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