Potions From Poisons

By ANDREA DORFMAN

If you're prospecting for new drugs in nature--which scientists continue to do, with or without the genome--there's no better place to start than the business end of a good poisonous plant or animal. Modern medicine is filled with drugs derived from deadly poisons, from the muscle relaxant curare (taken from South American vines that are used to poison arrow tips) to the anticoagulant Aggrastat (based on the venom of the saw-scaled viper).

The potency of these compounds is no accident. After all, each is part of an organism's defense and predatory mechanisms, whose specificity has been honed over millions of years of evolution. Animal venoms make particularly good sources of potential drugs because they are designed to kill or immobilize prey. Many contain dozens or even hundreds of potent, fast-acting toxins that home in on the muscles and nervous system. The molecules also tend to be small, which means they can easily slip across the blood-brain barrier, the network of tiny vessels in the brain that blocks larger compounds.

Poisonous snakes, spiders, scorpions and frogs have so far attracted the most scrutiny, but insects and marine creatures are also rich sources of potent compounds. Here's a taste of what's going on in the field.

Thailand (Monocled) Cobra

The Thailand cobra, which can grow to more than 6 ft., is armed with venom that paralyzes nerves and muscles and eventually causes respiratory arrest. For the past 10 years, PhyloMed Corp., of Plantation, Fla., and the Bahamian firm Coral Pharmaceuticals have been conducting clinical trials of Immunokine, a drug derived from Thailand cobra venom, on people with multiple sclerosis. Virtually nontoxic, Immunokine seems to prevent immune cells from attacking and destroying the myelin sheath that protects nerve cells.

So far, the results are encouraging. The drug works best on people with the least nerve damage; its only apparent side effect is that it exacerbates PMS in some women. PhyloMed hopes to launch a more advanced clinical trial on Canadian MS patients early this year. Meanwhile, a British researcher has just begun testing the drug's effectiveness against adrenomyeloneuropathy, another debilitating central-nervous-system disorder.

Phantasmal Poison-Dart Frog

In the early 1990s, John Daly, a biochemist at the National Institutes of Health, discovered that an extract from the skin of a tiny Ecuadorian tree frog was a potent pain killer, some 200 times more effective than morphine--at least in rats. The extract, known as epibatidine, is structurally and functionally similar to nicotine. It seems to prevent the nervous system from processing pain signals by interfering with nicotinic receptors in the brain.

When scientists at Abbott Laboratories heard about Daly's research, they compared epibatidine with several hundred related compounds they had synthesized as experimental treatments for Alzheimer's disease. One of them, ABT-594, turned out to be remarkably similar but much less toxic. Tests on animals indicate that ABT-594 is about 50 times better than morphine in relieving both chronic and acute pain yet seems to be nonaddictive. Phase II tests on humans should be completed by the end of the year.

Southern Copperhead

Scientists have long known that venom from the southern copperhead, native to the Eastern U.S. and Mexico, contains a powerful clot buster. In the mid-1990s, a team led by biochemist Francis Markland, of the University of Southern California, discovered that the venom may also fight cancer.

The venom contains a protein, contortrostatin, that retards the growth and metastasis of tumors. Markland's team has found that injections of contortrostatin not only prevent the spread of ovarian and breast tumors in mice but also shrink them as much as 75%. The group hopes to start clinical trials of contortrostatin in about two years.

Cone Snail

The tropical oceans harbor more than 500 species of cone snails, predatory creatures that stab their prey with harpoons loaded with a paralytic poison. Long prized by shell collectors, they are being scrutinized by drug hunters for potential treatments for neurological and neuromuscular disorders.

Each species of cone snail produces a unique venom that contains between 50 and 200 pharmacologically active peptides known as conotoxins. The most advanced conotoxin-derived drug in development is Elan Corp.'s Ziconotide, a nonaddictive treatment for severe chronic pain that is awaiting FDA approval. Cognetix, based in Salt Lake City, Utah, recently started clinical trials on a possible epilepsy treatment. Also in the works: potential therapies for schizophrenia, stroke and Parkinson's and Alzheimer's diseases.

Terciopelo Snake (Fer-de-Lance)

Pit-viper venoms--particularly those from the genus Bothrops, of which the Central American terciopelo snake is a member--contain compounds that closely resemble substances used by white blood cells to fend off bacterial infections. Some of these substances work by damaging or disrupting lipids within the bacterial cell wall. A decade ago, microbiologists Edgardo Moreno, of Costa Rica's National University, and Bruno Lomonte, of the University of Costa Rica, realized that a muscle-destroying toxin in terciopelo venom behaved the same way.

The two scientists have since isolated at least 10 microbe-fighting myotoxins from various viper venoms and synthesized nontoxic versions of them in the lab. They are talking to drug companies about doing additional research in animals and, eventually, people. If those studies pan out, Moreno says, viper-venom antibiotics could be put in everything from mouthwashes to contact lenses to fight salmonella, cholera, staph and strep.

Giant Israeli Scorpion

Chlorotoxin, a substance in the venom of the giant Israeli scorpion, a 5-in.-long species known as the "death stalker," may offer hope for the 25,000 Americans each year who have glioma, an incurable, rapidly spreading form of brain cancer. Surgery provides only a temporary respite, and the few experimental therapies extend a patient's life span only weeks.

Identified by neurobiologist Harald Sontheimer, of the University of Alabama at Birmingham, chlorotoxin targets glioma cells and blocks their fluid-balancing chloride channels, preventing them from shrinking and then migrating elsewhere in the brain. Sontheimer's group is about to submit a clinical-trial protocol to the FDA. If approved, as many as 30 glioma patients could begin receiving chlorotoxin tagged with radioactive iodine as early as July. If the strategy works, Sontheimer says, "chlorotoxin could become a platform for delivering all sorts of drugs."