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Venom as a Prelude to New Drug Treatments

By Rick Weiss
Washington Post Staff Writer
Monday, March 7, 2005; Page A08

Sixty million years after the earliest snakes figured out how to make venom in their salivary glands, descendants of the little mammals those snakes preyed on have begun to figure out just how the slithering reptiles did it.

And while it is too late for those who, in the intervening epochs, found themselves hyperventilating, bleeding, paralyzed or worse as a result of a run-in with a pair of fangs, it is not too late for the rest of us.

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A better understanding of what snake venoms are -- and how snakes cooked them up over eons of evolution -- promises better antivenins for future snakebite victims. But more important, it promises new drugs for cancer, heart disease and a variety of other ills, says Bryan Grieg Fry, a snake venom expert at the University of Melbourne in Australia. In a landmark article published this month, Fry traced the evolutionary roots of all the major poisons known to occur in snake venoms -- a feat that scientists said should facilitate a spectrum of biomedical discoveries.

Already, venoms from snakes and other creatures have led to the development of important medications, including the blood pressure drug captopril, which is a modified version of a toxin found in the green mamba of Africa.

Venoms have also proved their mettle in basic biomedical research -- their ill effects sometimes offering the first clue that there are biological systems in the body no one knew about. A toxin found in the deadly many-banded krait of Southeast Asia, for example, led to the discovery of an entire component of the human nervous system that had been unknown.

"Snakes are so inventive. Their venoms are a tremendous natural pharmacy," said Fry, who milks venom from 2,000 to 3,000 snakes a year and feels lucky to have been bitten only 24 times.

One of those bites launched Fry on his quest to understand the origins of snake venoms and, with luck, discover new medical applications. The culprit was a rare Stephen's banded snake, which Fry was trying to capture in the Australian rain forest.

"It knocked me out very quickly," Fry said. He collapsed in less than a minute. "As I was hitting the ground, I was thinking: 'Hmm, this is a rather unusual effect. If I survive this, I should be able to get a PhD out of it.' "

He did. After recovering, he analyzed the snake's venom and found that it was loaded with especially potent "natriuretic peptides," the class of proteins that in many animals -- including humans -- naturally help reduce blood pressure. "This explained the ability of the snake to knock me out so quickly," Fry said.

Fry went on to find that many snakes have versions of natriuretic toxins in their venoms, which are typically mixtures of toxins. He ended up with not only a doctorate but also a patent application for a version of the poison that may have potential as a treatment for congestive heart failure, a potentially fatal complication of high blood pressure.

But the finding also made Fry wonder: How many other snake toxins are "evil twins" of molecules that are normally helpful or even necessary to life? Biologists had long speculated that some snake toxins are chemical relatives of pancreatic enzymes. The pancreas, after all, is famed for its ability to digest all kinds of biological tissues, and many snakebite wounds end up looking like errant acts of digestion.

Might other toxins have similar roots?

To find out, Fry did something that was relatively simple but that no one else had done before. He knew that snake toxins are proteins, and proteins are long strings of amino acids, whose order determines the protein's shape and function. He compiled the amino acid sequences for all 24 of the major known snake toxins and, with a computer program, compared them with the sequences of all the other known proteins in snakes and other backboned creatures.

As reported in the March issue of the journal Genome Research, 23 of the 24 toxins were very close matches with proteins that have important functions in the bodies of vertebrates.

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