A new pain relief molecule from the sea.

A new pain relief molecule from the sea

By slightly modifying one of the components of the powerful venom concocted by the cones, marine gastropods, researchers have got a powerful painkiller. As effective as morphine, the less addictive, the α-conotoxin will surely become known.

The cones and their beautiful shells attract the diver and the collector of shells but connoisseurs are wary of this gastropod, dangerous poison. Scientists, for their part, are interested in venom, which is contained in the sort of tooth that harpoon the animal to hunt its prey, and is made up of conotoxins.

Indeed, α-conotoxins are known to have a painkilling action, comparable to that of morphine, with the advantage of not causing habituation. They act as inhibitors of nicotinic acetylcholine receptors in the nerves and muscles.

Doctors have long sought to use α-conotoxins as an analgesic treatment but their use is currently very modest. Its administration is complicated since the molecule must be directly introduced into the spinal cord of the patients.

Researchers at the Institute for Molecular Bioscience at the University of Queensland, Australia, published in the Angewandte Chemie International Edition journal results that promise a good deal of good weather in front of it. They have indeed managed to show the effectiveness of a peptide, derived from the α-conotoxin, usable by simple oral route. Their idea was to modify the structure of the molecule to make it, in a way, more solid.

A possible weapon against neuropathic pain

The strategy was to circularize the peptide, bringing together both ends of the protein. Usually, peptides are not or very little used as oral medications because they are very unstable and degraded in the digestive system before they can play their role. The fact that the protein is circularized makes it resistant to exopeptidases (enzymes that attack the protein ends) but also to endopeptidases (enzymes that cleave internal peptide bonds) through the strengthening of internal hydrogen bonds.

The two ends of a protein are frequently located close enough to each other: the addition of a few amino acids is enough to join the two ends. Here, the link between the two ends is composed of only six amino acids, including 2 alanines and 4 glycines. It was chosen for the low reactivity of these two amino acids. In addition, its low cost and ease of identification by nuclear magnetic resonance (NMR), were the other advantages.

The thus circularized peptide was tested in rats, in which the molecule was administered orally. The pain-killing efficacy of the circularized α-conotoxin is astonishing: it is as effective as the medication usually given in cases of severe pain (gabapentin) and it is sufficient to administer one hundredth of the usual dose!

Its small name, the α-conotoxin cVc1.1, is important. This peptide carries with it the hope of patients suffering from neuropathic pain, that is to say due to lesions of the nervous system, permanent and difficult to bear. For the time being, these patients are deprived of truly effective treatments.


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