Author
Listed:
- 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
University of North Carolina School of Medicine)
- Qianhui Qu
(Stanford University School of Medicine
Stanford University School of Medicine)
- Michael J. Robertson
(Stanford University School of Medicine
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
Rutgers New Jersey Medical School)
- Bryan L. Roth
(University of North Carolina School of Medicine)
- Jay P. McLaughlin
(University of Florida)
- Georgios Skiniotis
(Stanford University School of Medicine
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)
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.
Suggested Citation
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 , 2023.
"Structure-based design of bitopic ligands for the µ-opioid receptor,"
Nature, Nature, vol. 613(7945), pages 767-774, January.
Handle:
RePEc:nat:nature:v:613:y:2023:i:7945:d:10.1038_s41586-022-05588-y
DOI: 10.1038/s41586-022-05588-y
Download full text from publisher
As the access to this document is restricted, you may want to search for a different version of it.
Citations
Citations are extracted by the
CitEc Project, subscribe to its
RSS feed for this item.
Cited by:
- Lin Cheng & Zhuang Miao & Sicen Liu & Zhe Li & Hong Fu & Chanjuan Xu & Shilong Hu & Chang Zhao & Yuxuan Liu & Tiantian Zhao & Wencheng Liu & Heli Wang & Runduo Liu & Wei Yan & Xiangdong Tang & Jianfen, 2024.
"Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
- Václav Havel & Andrew C. Kruegel & Benjamin Bechand & Scot McIntosh & Leia Stallings & Alana Hodges & Madalee G. Wulf & Mel Nelson & Amanda Hunkele & Michael Ansonoff & John E. Pintar & Christopher Hw, 2024.
"Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models,"
Nature Communications, Nature, vol. 15(1), pages 1-21, December.
- Sandra Arroyo-Urea & Antonina L. Nazarova & Ángela Carrión-Antolí & Alessandro Bonifazi & Francisco O. Battiti & Jordy Homing Lam & Amy Hauck Newman & Vsevolod Katritch & Javier García-Nafría, 2024.
"A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site,"
Nature Communications, Nature, vol. 15(1), pages 1-13, December.
- Jun Yu & Amit Kumar & Xuefeng Zhang & Charlotte Martin & Kevin Van holsbeeck & Pierre Raia & Antoine Koehl & Toon Laeremans & Jan Steyaert & Aashish Manglik & Steven Ballet & Andreas Boland & Miriam S, 2024.
"Structural basis of μ-opioid receptor targeting by a nanobody antagonist,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
- Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024.
"Highly biased agonism for GPCR ligands via nanobody tethering,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:613:y:2023:i:7945:d:10.1038_s41586-022-05588-y. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.