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, and Dutertre, Sébastien (2021) Synthesis, structural and pharmacological characterizations of CIC, a novel α-conotoxin with an extended n-terminal tail. Marine Drugs, 19 (3). 141.

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Abstract

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.

Item ID: 70498
Item Type: Article (Research - C1)
ISSN: 1660-3397
Keywords: conotoxin, electrophysiology, nicotinic acetylcholine receptors, NMR structure, peptide synthesis
Copyright Information: © 2021 by the authors. 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 (https://creativecommons.org/licenses/by/4.0/).
Funders: Australian Research Council (ARC)
Projects and Grants: ARC LE160100218
Date Deposited: 15 Mar 2022 02:48
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320506 Medical biochemistry - proteins and peptides (incl. medical proteomics) @ 100%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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