Structure-based design of bitopic ligands for the μ-opioid receptor Journal Article
| Authors: | Faouzi, A.; Wang, H.; Zaidi, S. A.; DiBerto, J. F.; Che, T.; Qu, Q.; Robertson, M. J.; Madasu, M. K.; El Daibani, A.; Varga, B. R.; Zhang, T.; Ruiz, C.; Liu, S.; Xu, J.; Appourchaux, K.; Slocum, S. T.; Eans, S. O.; Cameron, M. D.; Al-Hasani, R.; Pan, Y. X.; Roth, B. L.; McLaughlin, J. P.; Skiniotis, G.; Katritch, V.; Kobilka, B. K.; Majumdar, S. |
| Article Title: | Structure-based design of bitopic ligands for the μ-opioid receptor |
| Abstract: | Mu-opioid receptor (μOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose1. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in μOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with μOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment—one (C6 guano) also shows the lowest Gz efficacy among the panel of μOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed μOR-dependent antinociception with attenuated adverse effects, supporting the μOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology. © 2022, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | unclassified drug; drug efficacy; nonhuman; drug targeting; mouse; animal; electron microscopy; metabolism; animals; mice; molecular dynamics; protein; in vivo study; protein interaction; structure activity relation; narcotic analgesic agent; public health; ligand; ligands; binding site; morphine; analgesics, opioid; molecular docking; g protein coupled receptor; mu opiate receptor; mu opiate receptor agonist; receptors, opioid, mu; analgesic agent; fentanyl; opiate receptor; cryoelectron microscopy; arrestins; antinociception; guanidine derivative; sodium ion; intrinsic activity; receptors, opioid; morphinan derivative; human; article; retina s antigen; design method; fentanyl derivative; morphinans; bitopic ligand; agonist potency |
| Journal Title: | Nature |
| Volume: | 613 |
| Issue: | 7945 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-01-26 |
| Start Page: | 767 |
| End Page: | 774 |
| Language: | English |
| DOI: | 10.1038/s41586-022-05588-y |
| PUBMED: | 36450356 |
| PROVIDER: | scopus |
| PMCID: | PMC10328120 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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