Nerve block: Halting pain at a snail's pace

Toxic snails

Conotoxins from the predatory cone snail work even at very low levels to block nerve signals. A new NMR spectroscopic study has investigated the structures of a specific conotoxin with a view to developing these compounds, or their derivatives, as novel painkillers.

You might say that the cone snail, Conus purpurascens, is a somewhat wily predator. It secretes itself away in the mud of its aquatic habitat, with just its wriggly proboscis protruding from the mud. Needless to say fish find this "worm" irresistible making the prey an easy target for the cone snail's venomous harpoon, essentially a modified tooth.

It was not the cone snail's harpoon, which is replaced after each meal, that was of interest to researchers at the Universities of Bonn and Jena, the Technical University of Darmstadt and the Leibniz Institute for Age Research in Jena, Germany, rather the toxic components of the cone snail venom. They have now identified the structure and mode of action of various forms of mu-conotoxin PIIIA. The details based on NMR spectroscopy and other approaches were reported in the journal Angewandte Chemie.

Team leader Diana Imhof of the University of Bonn's Pharmaceutical Institute explains their motivation. "We are interested in the cone snail's neurotoxins, the conotoxins." These agents are active in minute quantities and can interrupt the transmission of nerve signals very selectively. In the first instance this allows the cone snail to paralyse its harpooned prey and thus take its time to digest its meal. On the other hand, such selectivity might be exploited pharmacologically as a chemical agent for blocking the transmission of pain signals in people, especially those with chronic pain for whom conventional analgesic medication is no longer viable.

Non-dependent

"The advantage of these conotoxins is that they do not cause dependency," Imhof explains. "Since the peptide we studied decomposes rather quickly in the body, we do, however, need more stable forms that we can administer." Obviously, dependency is an important issue in the management of chronic pain, where a patient may need to take medication for many months or years.

The Bonn team worked with biophysicist Stefan Heinemann of the University of Jena and other colleagues to investigate mu-PIIIA specifically. The team was able to produce experimentally adequate quantities of this toxin for their NMR studies and to carry out in vitro analyses in the quest to understand its mode of action. In general, the conotoxins are peptides of 10 to 30 amino acids and typically have one or more bridging disulfide bonds that form rings rather than the peptide being a linear chain.

"This string can form clusters in different ways, forming diverse three-dimensional structures," explains Imhof. Until this work it was assumed that only one of the 3D forms was physiologically active, but the team has now reversed this dogma, showing that there are at least three active folds for the same peptide chain. Each form is slightly different in activity, but it is this variation that could be exploited in developing safe and active analgesics from the conotoxins.

With the structures to hand and increasing knowledge about biological activity, the next step will be to investigate these other fold variants of the mu-PIIIA conotoxin. As with much research in pharmaceutical science despite pressing ahead as quickly as possible developments usually come at a snail's pace.