title: Discovery of a new subclass of α-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 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.
authors.affiliation: Toxicology and Pharmacology, University of Leuven-KU Leuven, O&N2-P.O. Box 922, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Eline K M
authors.initials: EK
authors.lastname: Lebbe
authors.affiliation: Toxicology and Pharmacology, University of Leuven-KU Leuven, O&N2-P.O. Box 922, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.affiliation: Laboratory of Medicinal Chemistry, University of Leuven-KU Leuven, Rega Institute for Medical Research, Dept. of Pharmaceutical & Pharmacological Sciences, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Mohitosh
authors.initials: M
authors.lastname: Maiti
authors.affiliation: Toxicology and Pharmacology, University of Leuven-KU Leuven, O&N2-P.O. Box 922, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Bea G
authors.initials: BG
authors.lastname: Mille
authors.affiliation: CSIR-National Institute of Oceanography, Dona Paula, 403 004 Goa, India.
authors.forename: Prabha
authors.initials: P
authors.lastname: Devi
authors.affiliation: Center of Advanced Study in Marine Biology, Annamalai University, Parangipettai, 608 502 Tamil Nadu, India.
authors.forename: Samuthirapandian
authors.initials: S
authors.lastname: Ravichandran
authors.affiliation: Laboratory of Medicinal Chemistry, University of Leuven-KU Leuven, Rega Institute for Medical Research, Dept. of Pharmaceutical & Pharmacological Sciences, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.affiliation: Laboratorium voor Proteïne Fosforylatie en Proteomics, University of Leuven-KU Leuven, O&N I-P.O. Box 901, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.affiliation: CSIR-National Institute of Oceanography, Dona Paula, 403 004 Goa, India.
authors.forename: Lisette
authors.initials: L
authors.lastname: D'Souza
authors.affiliation: Laboratory of Medicinal Chemistry, University of Leuven-KU Leuven, Rega Institute for Medical Research, Dept. of Pharmaceutical & Pharmacological Sciences, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.affiliation: Toxicology and Pharmacology, University of Leuven-KU Leuven, O&N2-P.O. Box 922, Herestraat 49, 3000 Leuven, Belgium. Electronic address: jan.tytgat@pharm.kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000818:Animals; D020916:Conotoxins / Q000737:chemistry / Q000302:isolation & purification*; D052078:Conus Snail / Q000737:chemistry*; D008978:Mollusk Venoms / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular
chemical_list: D020916:Conotoxins; D008978:Mollusk Venoms
keywords: Cone snail; Conus australis; Electrophysiology; Neurological diseases; Nicotinic acetylcholine receptors; α-Conotoxins