Synthesis, Structural And Pharmacological Characterizations Of Cic, A Novel Alpha-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 alpha-conotoxins, targeting nicotinic acetylcholine receptors. Here, we report on the synthesis, structure determination and biological activity of a novel alpha-conotoxin, CIC, found in the predatory venom of the piscivorous species Conus catus and its truncated mutant Delta-CIC. CIC is a 4/7 alpha-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 Delta-CIC. Surprisingly, this effect on the structure does not alter the biological activity, since both peptides selectively inhibit alpha 3 beta 2 and alpha 6/alpha 3 beta 2 beta 3 nAChRs with almost identical sub- to low micromolar inhibition constants. Our results suggest that the N-terminal part of alpha-conotoxins can accommodate chemical modifications without affecting their pharmacology.