Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1783671246104297472 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8001506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT giribaldijulien synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT haufeyves synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT evansedwardrj synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT wilsondavidt synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT dalynorellel synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT enjalbalchristine synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT nickeannette synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail AT dutertresebastien synthesisstructuralandpharmacologicalcharacterizationsofcicanovelaconotoxinwithanextendednterminaltail |