More Deadly Than a Cobra; but Aids Parkinson’s Symptoms

What are the most poisonous creatures you can think of? Cobras? Scorpions? Japanese puffer fish? Now mix all these together and add 100 or so other nerve toxins. It sounds like a black magic witch's brew straight out of a fairy tale. Shockingly, it's a potion actually found in nature — in the venom of marine cone snails.

These snails live in the coral reefs surrounding Australia, Indonesia, and the Philippines. They use their venoms to hunt worms, other snails, or fish — some larger than themselves.

Each species of cone snail concocts its own unique venom containing dozens of nerve toxins. Some of these toxins instantly shock the prey, as does the sting of an electric eel or the poisons of scorpions and sea anemones. Others cause paralysis, like the venoms of cobras and puffer fish.

Cone snails use a variety of different hunting strategies. Some snails bury themselves in the sand and, when they smell a meal nearby, they extend a long, fleshy lure that attracts fish. Hidden in this wriggling, worm-like appendage is a sharp, barbed dart the snail uses to harpoon the prey and inject its venom. The snail then reels in the paralyzed fish and extends its mouth to engulf its catch.

Other snails open their mouths wide to capture entire schools of small fish. Then, at their leisure, the snails stab each of the unlucky swimmers with venom-filled darts. An hour or two later, the snails spit out all that remains of their meals — bones, scales, and the used harpoons.

In addition to their vast promise as a source of new drugs, cone snails are valued by collectors for their beautiful, intricately patterned shells. Some cone snail shells sell for thousands of dollars. According to one story, in 1796, a 2-inch-long shell fetched more at an auction than a painting by the famous Dutch artist Vermeer.

A Poison for Pain

One Conus peptide is already well on its journey to becoming a useful drug. Olivera originally called it omega-conotoxin MVIIA. Elan, which hopes to market the molecule, calls it by the generic name ziconotide. The peptide blocks calcium channels in one area of the spinal cord, preventing certain pain signals from reaching the brain. By testing the molecule in animals, scientists discovered that it is 1,000 times more powerful than morphine in treating certain types of pain. Even more exciting, it alleviates one type of pain, called neuropathic pain, for which morphine is inadequate.

Finally, it appears that ziconotide is free of morphine's fatal flaw — the development of tolerance. When people are given morphine for long periods of time, their bodies grow to "tolerate" the drug, requiring them to take more and more of it to provide pain relief. Ziconotide causes no such trouble. It appears to retain its potency without causing tolerance, even after prolonged use.

The peptide was tested initially on people with terminal cancer or AIDS. These trials were so successful that they were expanded to include other patients with severe, untreatable pain. Now the molecule is in phase III clinical trials — the last set required before requesting approval by the Food and Drug Administration (FDA).

It was discovered that the peptide that puts newborn mice to sleep locks onto a corner of one type of brain protein. That's about as specific as you can get. In fact, these peptides are so accurate in pinpointing their targets that they are now used by neuroscientists to identify and study specific brain proteins.

It's like identifying one child from a crowd of kids who all have the same color hair, eyes, and skin. If you were a parent of one of those kids, you'd have no trouble in picking your child out from the group. In a sense, that's what the toxins do.

Such specificity is irresistible to designers of new medicines. It holds the tantalizing promise of leading to a highly effective medication with very few side effects. For example, most "calcium channel blockers," which are medications used to treat high blood pressure, plug up calcium channels throughout the body, not just in the heart, where the drugs are needed. Conotoxins, on the other hand, seem to block only the calcium channels found in nerves, and not those in heart or other tissues. In this way, conotoxins could act as "smart" drugs that exert their effects only where they're needed, without spilling over to other bodily systems and potentially causing unwanted side effects.

Already, pharmaceutical companies are tapping the potential of dozens of cone snail peptides to treat disorders including pain, epilepsy, cardiovascular disease, and various neurological disorders. In addition to Cognetix, two other companies focus their business around the toxins — Elan Corporation, plc, in Dublin, Ireland, and Xenome Ltd. in Brisbane, Australia.

The clinical applications of Conus toxins are inspired by the snail's own biology. Paralyzing peptides might be used as anesthetics. "Sleepy" or "sluggish" peptides could be used as anti-epilepsy medications to tame nerve cells that fire out of control during seizures.

The long-term goal is to use the peptides to treat even more elusive conditions such as Alzheimer's, Parkinson's, schizophrenia, and depression. Who would have ever thought that the sluggish snail had so much potential for mankind?