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<p><i>μ</i>-Conotoxins target voltage-gated sodium channels, with KIIIA, CnIIIC, and SxIIIC showing notable inhibition of Na<sub>V</sub>1.7, which is strongly implicated in pain signaling. This study focuses on three such peptides—KIIIA, CnIIIC, and SxIIIC—and investigates their potential as analgesic according to the elucidation of their selectivity mechanism against different channel subtypes. Using computational simulations and pharmacological assays, we identified the critical role of the basic residues at the C-terminal of <i>μ</i>-conotoxin in binding to Na<sub>V</sub> channels. Two engineered mutants, R10E<sup>KIIIA</sup> and R20W<sup>CnIIIC</sup>, demonstrated significantly enhanced analgesic activity in vivo compared to their wild-type toxins. These findings highlight the potential of rational <i>μ</i>-conotoxin engineering for developing effective and safer pain therapeutics.</p> Graphical abstract <p></p> <p>Computational and pharmacological insights drive the enhancement of <i>μ</i>-conotoxin analgesic efficacy targeting human Na<sub>V</sub>s.</p>

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Study of enhancing analgesic potential of μ-conotoxins from the computational and pharmacological insights

  • 期刊论文

  • 发表日期：

    2026年4月4日

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  • Fan Zhao,
  • Yunxia Liu,
  • Ying Cui,
  • Yushan Ding,
  • Liu Ru,
  • Ting Meng,
  • Hongtao Yang,
  • Yongbo Song

摘要

μ-Conotoxins target voltage-gated sodium channels, with KIIIA, CnIIIC, and SxIIIC showing notable inhibition of NaV1.7, which is strongly implicated in pain signaling. This study focuses on three such peptides—KIIIA, CnIIIC, and SxIIIC—and investigates their potential as analgesic according to the elucidation of their selectivity mechanism against different channel subtypes. Using computational simulations and pharmacological assays, we identified the critical role of the basic residues at the C-terminal of μ-conotoxin in binding to NaV channels. Two engineered mutants, R10EKIIIA and R20WCnIIIC, demonstrated significantly enhanced analgesic activity in vivo compared to their wild-type toxins. These findings highlight the potential of rational μ-conotoxin engineering for developing effective and safer pain therapeutics.

Graphical abstract

Computational and pharmacological insights drive the enhancement of μ-conotoxin analgesic efficacy targeting human NaVs.