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Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail

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...

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Autores principales: Giribaldi, Julien, Haufe, Yves, Evans, Edward R. J., Wilson, David T., Daly, Norelle L., Enjalbal, Christine, Nicke, Annette, Dutertre, Sébastien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001506/
https://www.ncbi.nlm.nih.gov/pubmed/33801301
http://dx.doi.org/10.3390/md19030141
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author Giribaldi, Julien
Haufe, Yves
Evans, Edward R. J.
Wilson, David T.
Daly, Norelle L.
Enjalbal, Christine
Nicke, Annette
Dutertre, Sébastien
author_facet Giribaldi, Julien
Haufe, Yves
Evans, Edward R. J.
Wilson, David T.
Daly, Norelle L.
Enjalbal, Christine
Nicke, Annette
Dutertre, Sébastien
author_sort Giribaldi, Julien
collection PubMed
description 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.
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spelling pubmed-80015062021-03-28 Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail Giribaldi, Julien Haufe, Yves Evans, Edward R. J. Wilson, David T. Daly, Norelle L. Enjalbal, Christine Nicke, Annette Dutertre, Sébastien Mar Drugs Article 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. MDPI 2021-03-02 /pmc/articles/PMC8001506/ /pubmed/33801301 http://dx.doi.org/10.3390/md19030141 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Giribaldi, Julien
Haufe, Yves
Evans, Edward R. J.
Wilson, David T.
Daly, Norelle L.
Enjalbal, Christine
Nicke, Annette
Dutertre, Sébastien
Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail
title Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail
title_full Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail
title_fullStr Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail
title_full_unstemmed Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail
title_short Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail
title_sort synthesis, structural and pharmacological characterizations of cic, a novel α-conotoxin with an extended n-terminal tail
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001506/
https://www.ncbi.nlm.nih.gov/pubmed/33801301
http://dx.doi.org/10.3390/md19030141
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