Conotoxin truncation as a post-translational modification to increase the pharmacological diversity within the milked venom of Conus magus

Clifford A. Kapono, Parashar Thapa, Chino C. Cabalteja, Daniela Guendisch, Abby C. Collier, Jon Paul Bingham

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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. We demonstrate the presence of post-translational N-terminal peptide truncation, which differentiates the milked venom constituent α-conotoxin MI from the novel α-conotoxin MIC. This truncation has a direct effect on peptide bioactivity - Ki of 89.1±9.1 and 248.7±10.9nM (α-conotoxin MI and MIC respectively) toward the muscle-type nAChR (Torpedo). These milked venom conotoxins demonstrated acute lethality in fish, with a LD50 of 12.24 and 23.29μgkg-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±5.8nM and lethal toxicity level LD50 of 8.19μgkg-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.

Original languageEnglish (US)
Pages (from-to)170-178
Number of pages9
JournalToxicon
Volume70
DOIs
StatePublished - Aug 2013
Externally publishedYes

Keywords

  • α-Conotoxin
  • Conotoxins
  • Mass spectrometry
  • Milked venom
  • N-terminal modification
  • Post-translational modification

ASJC Scopus subject areas

  • Toxicology

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