Rational design of a Kappa opioid receptor peptide agonist with attenuated β-arrestin signaling.
basic_science · Level V
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- Record sourced from PubMed, PMID 41980950.
- Also identified by DOI 10.1038/s41467-026-71455-3.
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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 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.