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Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides
Sousa, S.R.; McArthur, J.R.; Brust, A.; Bhola, R.F.; Rosengren, K.J.; Ragnarsson, L.; Dutertre, S.; Alewood, P.F.; Christie, M.J.; Adams, D.J.; Vetter, I.; Lewis, R.J. (2018). Novel analgesic ω-conotoxins from the vermivorous cone snail Conus moncuri provide new insights into the evolution of conopeptides. NPG Scientific Reports 8(1): 15 pp. https://dx.doi.org/10.1038/s41598-018-31245-4
In: Scientific Reports (Nature Publishing Group). Nature Publishing Group: London. ISSN 2045-2322; e-ISSN 2045-2322
Peer reviewed article  
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  • Sousa, S.R.
  • McArthur, J.R.
  • Brust, A.
  • Bhola, R.F.
  • Rosengren, K.J.
  • Ragnarsson, L.
  • Dutertre, S.
  • Alewood, P.F.
  • Christie, M.J.
  • Adams, D.J.
  • Vetter, I.
  • Lewis, R.J.
Abstract
    Cone snails are a diverse group of predatory marine invertebrates that deploy remarkably complex venoms to rapidly paralyse worm, mollusc or fish prey. ω-Conotoxins are neurotoxic peptides from cone snail venoms that inhibit Cav2.2 voltage-gated calcium channel, demonstrating potential for pain management via intrathecal (IT) administration. Here, we isolated and characterized two novel ω-conotoxins, MoVIA and MoVIB from Conus moncuri, the first to be identified in vermivorous (worm-hunting) cone snails. MoVIA and MoVIB potently inhibited human Cav2.2 in fluorimetric assays and rat Cav2.2 in patch clamp studies, and both potently displaced radiolabeled ω-conotoxin GVIA (125I-GVIA) from human SH-SY5Y cells and fish brain membranes (IC50 2–9 pM). Intriguingly, an arginine at position 13 in MoVIA and MoVIB replaced the functionally critical tyrosine found in piscivorous ω-conotoxins. To investigate its role, we synthesized MoVIB-[R13Y] and MVIIA-[Y13R]. Interestingly, MVIIA-[Y13R] completely lost Cav2.2 activity and MoVIB-[R13Y] had reduced activity, indicating that Arg at position 13 was preferred in these vermivorous ω-conotoxins whereas tyrosine 13 is preferred in piscivorous ω-conotoxins. MoVIB reversed pain behavior in a rat neuropathic pain model, confirming that vermivorous cone snails are a new source of analgesic ω-conotoxins. Given vermivorous cone snails are ancestral to piscivorous species, our findings support the repurposing of defensive venom peptides in the evolution of piscivorous Conidae.
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