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 α-
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 α-
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 α-
conotoxin AusIA. The
peptide has the typical α-
conotoxin CC-Xm-C-Xn-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 α7 nAChR was the only receptor found to be blocked with a similar potency by both
peptide-configurations. This suggests that both α5/5
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 α-
conotoxin classification which might be helpful in the design of novel therapeutic compounds.