Toxicon : official journal of the International Society on Toxinology
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Milked venoms of Conus demonstrate direct lineage to US Food and Drug Administration approved and present in-trial drug leads. Yet the complexity of the milked venom has not been adequately investigated or characterized, in a sustainable manner. In this study we determine the extent of molecular mass differentiation in milked venom from captive Conus magus and confirm the expression of known conotoxin constituents. ⋯ These milked venom conotoxins demonstrated acute lethality in fish, with a LD₅₀ of 12.24 and 23.29 μg kg⁻¹ for α-conotoxin MI and MIC respectively. By synthesizing and investigating the synthetic intermediate variant des[Gly]¹α-conotoxin MI, it was demonstrated that retention of the N-terminal arginine residue increased affinity at the muscle-type nAChR site (binding Ki of 73.3 ± 5.8 nM and lethal toxicity level LD50 of 8.19 μg kg⁻¹). This post-translational modification event within the milked venom of C. magus represents a unique mechanism by which cone snails are able to increase the chemical and pharmacological diversity of their venoms.