Recently, a research team from the Hefei Institute of Physical Science of the Chinese Academy of Sciences (CAS), in collaboration with the Shanghai Institute of Materia Medica, CAS, developed a kappa opioid receptor (KOR) biased agonist with high efficacy and reduced side effects through structure-based rational design. The study was supported by the Steady High Magnetic Field Facility (SHMFF), including a 9.4 T magnetic resonance imaging system and an integrated experimental animal platform.
The results were published in Nature Communications.
Difelikefalin is a kappa opioid receptor (KOR) peptide agonist for the treatment of chronic pruritus. However, as a balanced agonist that activates both G protein and β-arrestin signaling pathways, it is still associated with side effects linked to β-arrestin signaling.
In this study, the researchers analyzed the cryo-electron microscopy structure of the difelikefalin–KOR–Gi complex and identified Y3207.43 as a key residue governed in signaling bias. Based on the structural analysis, they designed a peptide agonist, beta01, derived from β-amino acid substitutions, which strongly activates G protein signaling while recruiting minimal β-arrestin.
In mouse models, beta01 retained potent analgesic and antipruritic effects while significantly reducing sedation and anxiety-like behaviors, compared with difelikefalin. Structural and computational analyses, including molecular dynamics simulations and nuclear magnetic resonance spectroscopy, indicated that beta01 stabilizes KOR in a distinct conformation that reduces β-arrestin recruitment, providing a molecular basis for its improved safety profile.
This study establishes a structure-based rational design approach for biased KOR agonists, offering promising candidates for chronic pain and pruritus and providing a general framework for safer and more effective GPCR-targeted drug design.
Beta01 achieves G protein biased activation by remodeling the intracellular conformation of KOR. (Image by ZHU Qingjun)