Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-terminal Tail
| Autor: | David Wilson, Julien Giribaldi, Norelle L. Daly, Yves Haufe, Edward R. J. Evans, Sébastien Dutertre, Annette Nicke, Christine Enjalbal |
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| Přispěvatelé: | Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ludwig Maximilian University [Munich] (LMU), James Cook University (JCU), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Dutertre, Sébastien |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Conotoxin
[CHIM.ANAL] Chemical Sciences/Analytical chemistry Magnetic Resonance Spectroscopy Mutant Pharmaceutical Science Mollusk Venoms Venom Nicotinic Antagonists Receptors Nicotinic complex mixtures Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine [CHIM.ANAL]Chemical Sciences/Analytical chemistry Drug Discovery peptide synthesis Peptide synthesis Animals [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] lcsh:QH301-705.5 [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Pharmacology Toxicology and Pharmaceutics (miscellaneous) 030304 developmental biology Acetylcholine receptor 0303 health sciences biology Conus Snail Biological activity Conus catus biology.organism_classification electrophysiology Nicotinic agonist lcsh:Biology (General) MESH: Animals Conotoxins / chemistry Conotoxins / isolation & purification Conotoxins / pharmacology Conus Snail / metabolism chemistry MESH: Magnetic Resonance Spectroscopy Mollusk Venoms / chemistry Nicotinic Antagonists / isolation & purification Biophysics NMR structure nicotinic acetylcholine receptors Conotoxins MESH: Nicotinic Antagonists / pharmacology Receptors Nicotinic / drug effects Receptors Nicotinic / metabolism 030217 neurology & neurosurgery |
| Zdroj: | Marine Drugs Volume 19 Issue 3 Marine drugs Marine drugs, MDPI, 2021, 19 (3), pp.141. ⟨10.3390/md19030141⟩ Marine drugs, 2021, 19 (3), pp.141. ⟨10.3390/md19030141⟩ Marine Drugs, Vol 19, Iss 141, p 141 (2021) |
| ISSN: | 1660-3397 |
| DOI: | 10.3390/md19030141 |
| Popis: | International audience; Cone snails are venomous marine predators that rely on fast-acting venom to subdue their prey and defend against aggressors. The conotoxins produced in the venom gland are small disulfide-rich peptides with high affinity and selectivity for their pharmacological targets. A dominant group comprises α-conotoxins, targeting nicotinic acetylcholine receptors. Here, we report on the synthesis, structure determination and biological activity of a novel α-conotoxin, CIC, found in the predatory venom of the piscivorous species Conus catus and its truncated mutant Δ-CIC. CIC is a 4/7 α-conotoxin with an unusual extended N-terminal tail. High-resolution NMR spectroscopy shows a major influence of the N-terminal tail on the apparent rigidity of the three-dimensional structure of CIC compared to the more flexible Δ-CIC. Surprisingly, this effect on the structure does not alter the biological activity, since both peptides selectively inhibit α3β2 and α6/α3β2β3 nAChRs with almost identical sub- to low micromolar inhibition constants. Our results suggest that the N-terminal part of α-conotoxins can accommodate chemical modifications without affecting their pharmacology. |
| Databáze: | OpenAIRE |
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