An Onus on Conus

Bert Myers/Photo Researchers Inc.

This past December, the US Food and Drug Administration approved Prialt, Elan Corporation's synthetic version of a peptide from the venomous sea snail Conus magus. The drug, ziconotide, is the first of its kind and appears to alleviate severe pain by blocking N-type Ca⁺ channels.

Ziconotide is designed from one of about 100 pharmacologically active compounds in C. magus. And this undersea combinatorial chemist is only one of approximately 500 Conus species. Research on several of these peptides has turned up compounds with different modes of action, making them potentially useful in treating other types of pain.

But how these peptides relieve pain is still largely unclear. Moreover, ziconotide can only be delivered intrathecally to chronic pain patients who have no other options for relief and can cause cognitive impairment and hallucinations. Nevertheless, hope remains that the search for other peptides from Conus snails will bear fruit.

Baldomero Olivera and colleagues isolated w-conotoxin MVIIA, the natural version of ziconotide, at the University of Utah 25 years ago. The research team was looking to understand how the venom paralyzed fish, says Olivera. It wasn't until George Miljanich began investigating the drug at Neurex Corporation (which was later bought by Elan) that the therapeutic potential of ziconotide became apparent. It was ziconotide's molecular target being localized to spinal cord nerves that carry nociceptive signals that tipped them off, says Miljanich.

Ultimately, FDA approval of ziconotide is adding weight to the idea that Conus peptides are important sources of novel pain relievers. "Ziconotide confirmed N-channels as a key molecular target for analgesics," says Miljanich, "and that opens the door to the next generation of therapeutics directed against those targets." At least seven additional compounds are in clinical or preclinical trails at the moment.

Bruce Livett, a Conus snail researcher from the University of Melbourne, and his colleagues went about hunting for new conopeptides in the venom of Conus victoriae.¹ They screened cDNAs from the venom duct of C. victoriae and found the peptide Vc1.1, which competitively bound nicotinic acetylcholine receptors (nAChRs) and inhibited neurotransmitter release from neurons involved in pain transmission. Also named ACV1, the peptide is currently in preclinical trails with Metabolic Pharmaceuticals in Australia. "In this case, the molecular route, as opposed to isolating peptides directly from venom, worked well," says Livett.

In a similar fashion, Olivera and colleagues recently cloned a new peptide, a-conotoxin BuIA, from Conus bullatus, using polymerase chain reaction on venom duct cDNAs.² This Conus peptide is much more effective at blocking the b2 subunit of nAChRs, as opposed to the b4 subunit. Thus, BulA is a potential new probe for distinguishing between receptor subtypes, the functions of which are still not clear.

Rick Lewis, from the University of Queensland, isolated a 27-amino acid peptide form of Conus catus that also appears to block N-type Ca⁺ channels.³ Currently, this peptide, named AM366, is in stage II clinical trails with the Australian company Amrad. Other companies, including Xenome and Cognetix, are also pursuing the use of Conus peptides as pain relievers. But despite the drugs already being developed, Livett and Lewis believe the estimated 50,000 Conus peptides present in nature still hold many more surprises. "The work is a great proof of concept that conopeptides can be good drugs," says Lewis. "It is reinvigorating the area of drug discovery surrounding ion channels."