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

合理设计一种能减弱β-arrestin信号传导的Kappa阿片受体肽激动剂

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 Xu, Yue Wang, Changlin Tian (2026) Rational design of a Kappa opioid receptor peptide agonist with attenuated β-arrestin signaling. Nat Commun (IF: 15.7) 1 区

Abstract

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.© 2026. The Author(s).

地非利法林是一种经FDA批准的κ-阿片受体（KOR）肽激动剂，用于治疗慢性瘙痒。然而，作为一种平衡激动剂，地非利法林可同时激活G蛋白和β-arrestin通路，因此仍存在与β-arrestin信号通路相关的副作用。本文报道了地非利法林-KOR-Gi复合物的冷冻电镜结构，并鉴定出Y3207.43是影响信号偏向性的关键残基。基于此结构信息，我们设计了一种β-氨基酸取代的类似物β01，该类似物具有强效的G蛋白激活作用，但对β-arrestin的募集作用极小。在小鼠模型中，β01保留了强大的镇痛和止痒功效，同时显著降低了镇静作用和焦虑样行为。结构、分子动力学模拟和二维 13C-Met NMR 分析进一步揭示，β01 稳定了一种独特的 KOR 构象，其扩大的细胞内腔不利于 β-arrestin 的结合。这项工作为设计更安全、更有效的 GPCR 靶向治疗药物建立了一个基于结构的合理框架。© 2026. 作者。

Links

http://www.ncbi.nlm.nih.gov/pubmed/41980950
http://dx.doi.org/10.1038/s41467-026-71455-3

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