January 2011

ASBMB research on venom proteins

Now, researchers like Lewis are combining new technologies with established approaches to gain even more insight into the pharmacology of the varied venoms and other bioactive compounds present in the surrounding environment.

Lewis got his own introduction to this field in his doctoral research, where he studied ciguatoxin, a chemical produced by certain dinoflagellates that can accumulate in fish and cause ciguatera, a type of food poisoning. He then spent a few years in industry, working on ways to manage ciguatoxin poisoning, before taking a faculty position at the University of Queensland in 2000.

In his lab, Lewis has turned most of his attention to cone snails, remarkable predatory mollusks that have evolved a diverse set of toxin peptides that typically range from 10 to 30 amino acids long and are stabilized through disulfide bonds (though there are outliers, including a massive 11,000 kd dimer).

“Baldomero Olivera really helped break this field open in the early 1980s when he first isolated some of these peptides and assigned functions to them, and obviously, it would be difficult to compete with him,” Lewis says. “But I thought if I focused on some of our distinct Australian cone sail species, our group could make a unique contribution.”

That certainly has been the case; while most characterized conotoxins have roles in blocking ion channel activity, Lewis’ team has found some more unusual inhibitors, such as peptides that block a G-protein coupled receptor and the norepinephrine (noradrenaline) transporter.

The latter peptide, part of a new family called chi-conopeptides, was particularly exciting. “Norepinephrine is involved in one of the key analgesic pathways in the spinal cord known as descending inhibition,” Lewis notes. “And when we did test the peptide in animals we found that it had some dramatic pain-relieving effects in models of neuropathic pain, which is exciting since neuropathic pain remains poorly treated in humans.”

Along with some colleagues, Lewis spun his discoveries into a startup biotech called Xenome, which is hoping to take his chi-conopeptide (Xen2174) into the clinic along with other leads like new calcium channel-blocking omega-conopeptides recently discovered through a National Health and Medical Research Council program grant. These new omegas have strong analgesic properties but none of the side effects typically seen in this class of peptides.

Recently, Lewis has been looking into integrating mass spectrometry technology and deep sequencing to probe cone snail peptides in even greater detail.

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