Author:

Keywords:

cone snail, conotoxin

Abstract:

Cone snails are predatory creatures using venom as a weapon for prey capture and defense. Since this venom is neurotoxic, the venom gland is considered as an enormous collection of pharmacologically interesting compounds with a broad spectrum of targets. As such, cone snail peptides represent an interesting treasure for drug development. Here we report two novel peptides isolated from the venom of Conus australis. The first peptide, a disulfide poor conopeptide, has only one disulfide bridge (GAYFDGFDVPCVPRRDDC). The molecular mass was determined to be 2.032,24 Da, perfectly fitting the primary sequence. The peptide, named AusB, was electrophysiologically tested on a panel of NaVs, KVs and nAChRs as expressed heterologously in Xenopus laevis oocytes, but up to now, no target could be identified nor could the peptide be classified. The second peptide is an α-conotoxin and named AusIA according to its classification (SCCARNPACRHNHPCV). Remarkably, both intercystein loops of AusIA consist out of five amino acids (α5/5), which has never been described before. Typically, α-conotoxins target nicotine acetylcholine receptors (nAChRs) and dysfunctions of nAChRs have important roles in several pathologies such as epilepsy, schizophrenia, Parkinson's disease and Alzheimer's disease. This explains the general interest in ‘cono-toxinology’ since many years now. We investigated the response of synthetically made globular (I-III, II-IV) and ribbon (I-IV, II-III) AusIA to different nAChRs. The α7 nAChR was the only receptor found to be blocked by both peptide-configurations. NMR spectroscopy showed that no secondary structures are included in the peptides' three-dimensional topology. This is rather atypical as compared to other α-conotoxins. Moreover, the ribbon configuration, which is generally considered to be non-native, is more stable than the globular isomer. Taken together, we believe that the venom of C. australis is a precious source for new insights in ‘cono-toxinology’.