Cone snail toxins can be deadly to humans – but they also have potential uses in anaesthesia and to treat other medical conditions. This latest Chemunicate graphic takes a look at one way scientists are trying to optimise them for this use.
Conotoxin peptides are compounds isolated from fish-hunting cone snails. They are the toxic components of cone snail venom and have been recorded as causing several human fatalities.
Despite their toxicity, conotoxin peptides have the potential for use as muscle relaxants for anaesthesia. They induce muscle relaxation by binding to nACh receptors. The fact that these receptors are also found in the nervous system leads to their unwanted toxic effects.
A particular conotoxin peptide, α–Conotoxin GI (GI), avoids these toxic side effects. However, its reactivity and poor stability in the bloodstream limit its potential use as a muscle relaxant. In particular, the reaction of the disulfide bond bridges can cause the shape of GI to change, meaning it is no longer the correct shape to bind to nACh receptors and exert its medical effects.
In this work, researchers replaced the disulfide bridges in GI with 1,2,3 triazole bridges. This mimics the shape and arrangement of the disulfide bond. This modification significantly increased the stability of GI in human cells, keeping it held in the correct shape for it to retain its full biological activity.
The fact that the modification was easy to achieve with commercially available reagents means that it may be applicable to other peptides containing disulfide bonds, including other conotoxins. In the case of GI, tests in human cells confirmed that the modified structure retained its efficacy, giving it potential as a safe and reversible muscle relaxant for use in anaesthesia. The NMR method used to determine GI’s structure could also help inform future drug discovery efforts.