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Painkiller from the sea

By Graeme O'Neil

<Sunday Herald Sun, April 21, 1996, p. 5>

(transcribed and annotated by Dr. Bruce Livett)

The venom of some of the Pacific Ocean's cone shells, has shown extraordinary promise in controlling chronic pain.

Recent experiments in the United States have shown a synthetic molecule based on one of the paralyzing neurotoxins in the venom of the magician's cone shell , almost magically blocks acute pain in patients who no longer obtain relief from opiate drugs (see References below). These include terminally ill cancer and AIDS patients with chronic pain and long-term amputees with "phantom limbs".

Dr. William Brose, director of a pain clinic at Stanford University School of Medicine in San Francisco (see protocol #486), says the compound called SNX-111, developed by the biopharmaceutical company Neurex, is 100 to 1000 times more potent than morphine.

Cone shell venom expert Professor Jim Angus of Melbourne University's Department of Pharmacology, describes the US research as a "tour de force", and says Australia stands to reap a bonanza from the venoms of its own cone shells - there are now more than 70 species on the Great Barrier Reef and many others around the Australian coast, including several in Victorian waters.

Australian researchers are doing "fantastic work" on the rich cocktail of neurotoxins in native cone shell venoms. Prof. Angus's research team has been studying cone shell venoms for more than five years to determine their effect on nerves and muscles.

Another team, headed by Dr. Bruce Livett at the Department of Biochemistry and Molecular Biology at Melbourne University is collaborating with Dr. Paul Alewood and colleagues at the Centre for Drug Design and Development in Brisbane (Director, Dr. Peter Andrews).

Various Conus species paralyze and eat a wide range of marine creatures including fish, worms and other molluscs. They extend a proboscis-like organ with a harpoon-like tip, firing venom into their prey, inducing paralysis and death in seconds.

Cone shells have killed humans who have innocently picked them up - the geographers cone, Conus geographus , found on the Great Barrier Reef, has killed at least 20 people in Australia and the western Pacific.

Western medical researchers initially became interested in conotoxins when a medical researcher at the University of the Philippines in Manila,
Dr. Baldomero Olivera , reported some species could paralyze fish within seconds.

Prof. Angus says cone shell venoms very enormously in composition. The venom of some species contains up to 90 different peptides - small protein fragments - that exhibit powerful, highly selective activity on nerves.

"They seem to change their peptide fingerprints almost at whim," Prof. Angus said.

"From day to day, the proportion of peptides changes, and new compounds appear while others disappear from the venom".

The cone shell's strategy in proving a bonanza for drug researchers looking for new painkillers - the tiny peptide molecules have highly specific effects on a wide range of molecular targets in nerve cells.

Neurex's prototype drug SNX-111 now in the final stages of clinical testing before commercial release, is an N-type calcium channel blocker , omega conotoxin MVIIa [The omega conotoxin MVIIa structure, (PDB file), can be found in the PDB, ID code 1omg. Click here for a full scientific paper on the structure (by NMR) and related papers ].

[Follow these links for a scientific article about the NMR solution structure of a related omega conotoxin conotoxin MVIIc , a 'P'-type calcium channel blocker from Conus magus, and a molecular graphic of conotoxin MVIIc . For a larger annotated molecular graphic (takes some time to download), see big molecular graphic . The omega-conotoxin MVIIC structure can be found in the PDB, ID code 1OMN, T7094 for the coordinates T7905 for the restraints].

Prof Angus says nerves are activated by an influx of calcium ions to the cell's interior, which in turn triggers the release of compounds that transmit signals between nerves, including the signals that carry pain.

The SNX-111 conotoxin molecule is just the right size and shape to block the tiny pores in the nerve cell's membrane through which the calcium ions flow - with the calcium channels blocked, the nerve can not transmit pain signals and the patient is relieved.

Most patients with intractable pain eventually become tolerant of powerful opiate drugs such as morphine and pethidine, even at dosages 1000 times higher than those that would kill a normal person.

Dr. Brose's Stanford study infused SNX-111 directly into the spine of seven volunteers, who had suffered chronic pain for more than 35 years after amputations or nerve damage.

They used a tiny pump that delivers a constant dosage of the drug. After three days, five of the seven patients reported their pain had disappeared.

The only side-effects were mild eye jitters and a slight drop in blood pressure - patients on heavy doses of opiates are normally lethargic and suffer impaired intellectual function.

One female patient was able to reduce the daily cost of her opiate drugs from $6000 to only $100; SNX-111 seemed to reverse her tolerance of opiates.

The US researches used direct-infusion because peptides tend to break down in the digestive system.

Prof Andrews' team in Brisbane is trying to develop synthetic, oral analogues of conotoxins - drugs that mimic the action of the natural conotoxins, but which would be absorbed through the digestive tract without breaking down.

References:

Buchan, A. M. et al. (1994) J. Cereb. Blood Flow Metab., 14, 903-910.

Concar, D. (1996) "Doctor snail". New Scientist, 19 October, 278: pp.26-28.

Gibbs, W.W. (1996) A new way to spell relief: V-e-n-o-m. A toxin from killer sea snails promises a better painkiller ". Scientific American 274 (2) February (1996), 20-21.

Olivera BM., Cruz LJ., de Santos V., LeCheminant GW., Griffin D., Zeikus R., McIntosh JM., Galyean R., Varga J., Gray WR., et al (1987) Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry 26: 2086-90.

Smith, M. L. and Siesjo, B. K (1992) in Pharmacology of Cerebral Ischemia (Krieglstein, J. and Oberpilcher, H., Eds) pp. 161-167, Wissenschaftiliche Verlagsgesellschaft Stuttgart, Germany.  


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