Scholarlink

<p>Difelikefalin is an FDA-approved κ-opioid receptor (KOR) peptide agonist used to treat chronic pruritus. However, as a balanced agonist that activates both G protein and β-arrestin pathways, difelikefalin remains associated with undesirable side effects linked to β-arrestin signaling. Here, we report the cryo-EM structure of the difelikefalin-KOR-Gi complex, identifying Y320<sup>7.43</sup> as a key residue that is critical for signaling bias. Guided by this structural insight, we engineer beta01, a β-amino acid-substituted analog with potent G protein activation but minimal β-arrestin recruitment. In mouse models, beta01 retains robust antinociceptive and antipruritic efficacy while significantly reducing sedation and anxiety-like behaviors. Structural, molecular dynamics simulations and 2D <sup>13</sup>C-Met NMR analyses further reveal beta01 stabilizes a unique KOR conformation with an expanded intracellular cavity that disfavors β-arrestin binding. This work establishes a rational structure-based framework for designing safer and more effective GPCR-targeted therapeutics.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Rational design of a Kappa opioid receptor peptide agonist with attenuated β-arrestin signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月14日

查看全文
  • Huanhuan Zhang,
  • Ruolan Wang,
  • Pan Shi,
  • Gaoming Wang,
  • Qingjun Zhu,
  • Xinheng He,
  • Youwei Xu,
  • Qingning Yuan,
  • Wen Hu,
  • Kai Wu,
  • Yong Zheng,
  • Li Zhou,
  • Jun Liang,
  • Pei Lv,
  • Ziyan Xu,
  • Fan Yang,
  • Yingbin Liu,
  • Youwen Zhuang,
  • H. Eric Xu,
  • Yue Wang,
  • Changlin Tian

摘要

Difelikefalin is an FDA-approved κ-opioid receptor (KOR) peptide agonist used to treat chronic pruritus. However, as a balanced agonist that activates both G protein and β-arrestin pathways, difelikefalin remains associated with undesirable side effects linked to β-arrestin signaling. Here, we report the cryo-EM structure of the difelikefalin-KOR-Gi complex, identifying Y3207.43 as a key residue that is critical for signaling bias. Guided by this structural insight, we engineer beta01, a β-amino acid-substituted analog with potent G protein activation but minimal β-arrestin recruitment. In mouse models, beta01 retains robust antinociceptive and antipruritic efficacy while significantly reducing sedation and anxiety-like behaviors. Structural, molecular dynamics simulations and 2D 13C-Met NMR analyses further reveal beta01 stabilizes a unique KOR conformation with an expanded intracellular cavity that disfavors β-arrestin binding. This work establishes a rational structure-based framework for designing safer and more effective GPCR-targeted therapeutics.