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Study · Not a test of the peptide alone · 2026

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

Zhang H, Wang R, Shi P, Wang G, Zhu Q, He X, Xu Y, Yuan Q, Hu W, Wu K, Zheng Y, Zhou L and 9 more

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Liang J, Lv P, Xu Z, Yang F, Liu Y, Zhuang Y, Xu HE, Wang Y, Tian C

Nature communications14 Apr 2026Cited by 1 (Europe PMC)

PMID41980950 (opens in a new tab)PMCIDPMC13279772 (opens in a new tab)DOI10.1038/s41467-026-71455-3 (opens in a new tab)PepBankPUB-41980950
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Summary

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.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone1

In this study, Difelikefalin was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Difelikefalin.

  1. 01LabNot a test of Difelikefalin aloneIn vitro (cell-free)Mechanism

    In laboratory structural analyses, the difelikefalin-KOR-Gi complex identified Y320 as a residue critical for signaling bias.

    In plain wordsIn lab tests, the difelikefalin receptor complex identified a residue critical for signaling bias.

    Peptide
    Difelikefalin
    Outcome
    Not applicableDifelikefalin-KOR-Gi structure
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    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.

    In this study, Difelikefalin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Difelikefalin.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    28 Oct 2026, 02:03 UTC

    Study results updated

  2. Version 1

    27 Oct 2026, 16:35 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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