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<p>The χ-conotoxins are venom-derived peptides that specifically target the noradrenaline transporter (also known as norepinephrine transporter, NET). Regulation of noradrenergic signaling by NET affects neurophysiological processes, including pain. Therefore, the χ-conotoxin MrIA and its synthetic analogs have been previously investigated for their analgesic activity. Here we describe the synthesis and pharmacological characterization of χ-AoIA, a peptide that selectively inhibits NET with a higher potency compared to MrIA in in vitro radiotracer flux assays. Furthermore, we resolved the structure of the human NET:χ-AoIA complex by cryogenic electron microscopy, which revealed an atypical binding mode consisting of both the central binding site and the outer vestibule of the transporter. Lastly, χ-AoIA displays antinociceptive efficacy in a model of inflammatory pain after subcutaneous administration in mice. Our results demonstrate the efficacy of χ-AoIA as a highly selective ligand of NET and provide a mechanistic basis for its potential development as a nonopioid analgesic.</p>

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Structural and functional basis of antinociceptive action of χ-conotoxin AoIA at the noradrenaline transporter

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Oliver J. V. Belleza,
  • Heng Zhang,
  • Helmut Schmidhammer,
  • Tye I. Gonzalez,
  • Cosmin I. Ciotu,
  • Nataša Tomašević,
  • Carlo Martin M. Ocampo,
  • Jomari C. Fernando,
  • Johannes Koehbach,
  • Paula Schwarz,
  • Mounaf Al Makhlouf,
  • Gabor Tajti,
  • Simon Hasinger,
  • Nina Kastner,
  • Orcun Avsar,
  • Bernhard Retzl,
  • Kathrin Jäntsch,
  • Yi Jiang,
  • Roland Hellinger,
  • Michael J. M. Fischer,
  • K. Johan Rosengren,
  • Christian W. Gruber,
  • Aaron Joseph L. Villaraza,
  • Thomas Stockner,
  • Mariana Spetea,
  • H. Eric Xu,
  • Harald H. Sitte

摘要

The χ-conotoxins are venom-derived peptides that specifically target the noradrenaline transporter (also known as norepinephrine transporter, NET). Regulation of noradrenergic signaling by NET affects neurophysiological processes, including pain. Therefore, the χ-conotoxin MrIA and its synthetic analogs have been previously investigated for their analgesic activity. Here we describe the synthesis and pharmacological characterization of χ-AoIA, a peptide that selectively inhibits NET with a higher potency compared to MrIA in in vitro radiotracer flux assays. Furthermore, we resolved the structure of the human NET:χ-AoIA complex by cryogenic electron microscopy, which revealed an atypical binding mode consisting of both the central binding site and the outer vestibule of the transporter. Lastly, χ-AoIA displays antinociceptive efficacy in a model of inflammatory pain after subcutaneous administration in mice. Our results demonstrate the efficacy of χ-AoIA as a highly selective ligand of NET and provide a mechanistic basis for its potential development as a nonopioid analgesic.