Structure-based design of bitopic ligands for the µ-opioid receptor

Abdelfattah Faouzi, Haoqing Wang, Saheem A. Zaidi, Jeffrey F. DiBerto, Tao Che, Qianhui Qu, Michael J. Robertson, Manish K. Madasu, Amal El Daibani, Balazs R. Varga, Tiffany Zhang, Claudia Ruiz, Shan Liu, Jin Xu, Kevin Appourchaux, Samuel T. Slocum, Shainnel O. Eans, Michael D. Cameron, Ream Al-Hasani, Ying Xian Pan, Bryan L. Roth, Jay P. McLaughlin, Georgios Skiniotis (), Vsevolod Katritch (), Brian K. Kobilka () and Susruta Majumdar ()
Additional contact information
Abdelfattah Faouzi: University of Health Sciences and Pharmacy and Washington University School of Medicine
Haoqing Wang: Stanford University School of Medicine
Saheem A. Zaidi: University of Southern California
Jeffrey F. DiBerto: University of North Carolina School of Medicine
Tao Che: University of Health Sciences and Pharmacy and Washington University School of Medicine
Qianhui Qu: Stanford University School of Medicine
Michael J. Robertson: Stanford University School of Medicine
Manish K. Madasu: University of Health Sciences and Pharmacy and Washington University School of Medicine
Amal El Daibani: University of Health Sciences and Pharmacy and Washington University School of Medicine
Balazs R. Varga: University of Health Sciences and Pharmacy and Washington University School of Medicine
Tiffany Zhang: Memorial Sloan Kettering Cancer Center
Claudia Ruiz: Scripps Research
Shan Liu: Rutgers New Jersey Medical School
Jin Xu: Rutgers New Jersey Medical School
Kevin Appourchaux: University of Health Sciences and Pharmacy and Washington University School of Medicine
Samuel T. Slocum: University of North Carolina School of Medicine
Shainnel O. Eans: University of Florida
Michael D. Cameron: Scripps Research
Ream Al-Hasani: University of Health Sciences and Pharmacy and Washington University School of Medicine
Ying Xian Pan: Memorial Sloan Kettering Cancer Center
Bryan L. Roth: University of North Carolina School of Medicine
Jay P. McLaughlin: University of Florida
Georgios Skiniotis: Stanford University School of Medicine
Vsevolod Katritch: University of Southern California
Brian K. Kobilka: Stanford University School of Medicine
Susruta Majumdar: University of Health Sciences and Pharmacy and Washington University School of Medicine

Nature, 2023, vol. 613, issue 7945, 767-774

Abstract: 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.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05588-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:613:y:2023:i:7945:d:10.1038_s41586-022-05588-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05588-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().