The recently FDA-approved severe pain drug, Prialt (ziconotide intrathecal infusion), from Elan Corp., Dublin, Ireland, contains a synthetic analog of a peptide derived from a venomous marine snail. The peptide was first discovered 25 years ago by an undergraduate student, Michael McIntosh, at the University of Utah. who worked in the lab of Baldomero Olivera, PhD. Olivera, a professor of biology, still studies the Conus magus cone snails for their drug-producing potential and is very familiar with the challenges involved in their use.
“These snails are not very large,” says Olivera. Once the snails are collected, they are dissected for the venom ducts. “You end up with very little material,” he says. They address that by using material in the snail venom only to determine structure and sparingly for assaying function, until the complete structure is determined. In the venom there are 100 to 200 different components. The first difficult step is purifying out the component of interest, says Olivera. “Then, once the structure is determined, we will synthesize it and cut loose in determining function.”
Determining the structure of the peptides was originally much more difficult at the time of this discovery, says Olivera, because the methods required much more material to work with. The process is quite efficient these days, he says, because the active substances are mostly peptides and the technology for determining structure and synthesizing them is there. This, however, leads to the second problem in the drug development stage. “Drug companies don’t like peptides and I think that is part of the reason why it took so long for this drug to get approved.”
“It turns out that almost all of these peptides, including the one in Prialt, have disulfide cross-links and forming those cross links correctly is important because they are what gives the compound its structure. “One of the standard amino acids, cysteine, is responsible for disulfide cross-links. If there are six cysteines, as Prialt has, then there are 15 possible ways to cross-link them and only one of those isomers is the biologically active form, so it must be formed correctly. If they are not formed correctly, the compound will not have a high affinity for its pharmacological target. The actual chemical synthesis is relatively easy but making the correctly crossed-linked isomer is the greatest challenge, he says.
“Prialt came from one particular cone snail, and it was one of the approximately 100 different components of the venom of that cone snail,” says Olivera. “There are 500 different species of cone snails and each one has an entirely different set of compounds, so the total pharmacological resource is huge, among 50,000 compounds.”
McIntosh is now a professor of psychiatry and research professor of biology at the university and directs research in the Department of Psychiatry at the University of Utah Health Science Center.
By Elizabeth Tolchin