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

Julien Giribaldi (1) , Yves Haufe (2) , Edward Evans (3) , David Wilson (3) , Norelle Daly (3) , Christine Enjalbal (1) , Annette Nicke (2) , Sébastien Dutertre (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
3 JCU - James Cook University

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.

Mots clés: NMR structure; Conotoxin; Electrophysiology; Nicotinic acetylcholine receptors; Peptide synthesis

Domaines: Chimie analytique; Biochimie [q-bio.BM]

Julien Giribaldi, Yves Haufe, Edward Evans, David Wilson, Norelle Daly, et al.. Synthesis, Structural and Pharmacological Characterizations of CIC, a Novel α-Conotoxin with an Extended N-Terminal Tail. Marine drugs, 2021, 19 (3), pp.141. ⟨10.3390/md19030141⟩. ⟨hal-03440279⟩