Discovery of a new subclass of alpha-conotoxins in the venom of Conus australis

Abstract

Cone snails (Conus sp.) are poisonous animals that can be found in all oceans where they developed a venomous strategy to prey or to defend. The venom of these species contains an undeniable source of unique and potent pharmacologically active compounds. Their peptide compounds, called conotoxins, are not only interesting for the development of new pharmaceutical ligands, but they are also useful for studying their broad spectrum of targets. One conotoxin family in particular, the alpha-conotoxins, acts on nicotinic acetylcholine receptors (nAChRs) which dysfunctions play important roles in pathologies such as epilepsy, myasthenic syndromes, schizophrenia, Parkinson's disease and Alzheimer's disease. Here we define a new subclass of the alpha-conotoxin family. We purified the venom of a yet unexplored cone snail species, i.e. Conus australis, and we isolated a 16-amino acid peptide named alpha-conotoxin AusIA. The peptide has the typical alpha-conotoxin CC-X_m-C-X_n-C framework, but both loops (m/n) contain 5 amino acids, which has never been described before. Using conventional electrophysiology we investigated the response of synthetically made globular (I–III, II–IV) and ribbon (I–IV, II–III) AusIA to different nicotinic acetylcholine receptors. The alpha 7 nAChR was the only receptor found to be blocked with a similar potency by both peptide-configurations. This suggests that both alpha 5/5 conotoxin isomers might be present in the venom gland of C. australis. NMR spectroscopy showed that no secondary structures define the peptides' three-dimensional topology. Moreover, the ribbon configuration, which is generally considered to be non-native, is more stable than the globular isomer. Accordingly, our findings show relevancy concerning the alpha-conotoxin classification which might be helpful in the design of novel therapeutic compounds