title: δ-Conotoxins synthesized using an acid-cleavable solubility tag approach reveal key structural determinants for NaV subtype selectivity.
abstract: Conotoxins are venom peptides from cone snails with multiple disulfide bridges that provide a rigid structural scaffold. Typically acting on ion channels implicated in neurotransmission, conotoxins are of interest both as tools for pharmacological studies and as potential new medicines. δ-Conotoxins act by inhibiting inactivation of voltage-gated sodium channels (Nav). Their pharmacology has not been extensively studied because their highly hydrophobic character makes them difficult targets for chemical synthesis. Here we adopted an acid-cleavable solubility tag strategy that facilitated synthesis, purification, and directed disulfide bridge formation. Using this approach we readily produced three native δ-conotoxins from Conus consors plus two rationally designed hybrid peptides. We observed striking differences in Nav subtype selectivity across this group of compounds, which differ in primary structure at only three positions: 12, 23, and 25. Our results provide new insights into the structure-activity relationships underlying the Nav subtype selectivity of δ-conotoxins. Use of the acid-cleavable solubility tag strategy should facilitate synthesis of other hydrophobic peptides with complex disulfide bridge patterns.
authors.affiliation: From the Department Pharmaceutical Sciences, Laboratory of Toxicology & Pharmacology, Catholic University, 3000 Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.affiliation: the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Paolini-Bertrand
authors.affiliation: the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gaertner
authors.affiliation: Atheris Laboratories, 1233 Bernex, Switzerland, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Biass
authors.affiliation: Atheris Laboratories, 1233 Bernex, Switzerland, and.
authors.forename: Aude
authors.initials: A
authors.lastname: Violette
authors.affiliation: Atheris Laboratories, 1233 Bernex, Switzerland, and.
authors.forename: Reto
authors.initials: R
authors.lastname: Stöcklin
authors.affiliation: Atheris Laboratories, 1233 Bernex, Switzerland, and the Department of Environment, Transport and Agriculture, Service de Toxicologie de l'Environnement, 1211 Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Favreau
authors.affiliation: From the Department Pharmaceutical Sciences, Laboratory of Toxicology & Pharmacology, Catholic University, 3000 Leuven, Belgium, jan.tytgat@pharm.kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.affiliation: the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland, oliver.hartley@unige.ch.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
mesh_terms: D000143:Acids / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020916:Conotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052078:Conus Snail / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D000143:Acids; D020916:Conotoxins; D004220:Disulfides; D010446:Peptide Fragments; D020033:Protein Isoforms; D061566:Voltage-Gated Sodium Channels
keywords: Conotoxin; Molecular Pharmacology; Natural Product Biosynthesis; Neurotoxin; Peptide Chemical Synthesis; Sodium Channel