A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor

Dekan, Zoltan; Sianati, Setareh; Yousuf, Arsalan; Sutcliffe, Katy J.; Gillis, Alexander; Mallet, Christian; Singh, Paramjit; Jin, Aihua H.; Wang, Anna M.; Mohammadi, Sarasa A.; Stewart, Michael; Ratnayake, Ranjala; Fontaine, Frank; Lacey, Earnest; Piggott, Andrew M.; Du, Yan P.; Canals, Meritxell; Sessions, Richard B.; Kelly, Eamonn .; Capon, Robert J.; Alewood, Paul F.; Christie, MacDonald J.

Abstract

An Australian estuarine isolate ofPenicilliumsp. MST-MF667 yielded3 tetrapeptides named the bilaids with an unusual alternating LDLDchirality. Given their resemblance to known short peptide opioidagonists, we elucidated that they were weak (Kilow micromolar)?-opioid agonists, which led to the design of bilorphin, a potent andselective?-opioid receptor (MOPr) agonist (Ki1.1 nM). In sharp con-trast to all-natural product opioid peptides that efficaciously recruit?-arrestin, bilorphin is G protein biased, weakly phosphorylatingthe MOPr and marginally recruiting?-arrestin, with no receptorinternalization. Importantly, bilorphin exhibits a similar G proteinbias to oliceridine, a small nonpeptide with improved overdosesafety. Molecular dynamics simulations of bilorphin and thestrongly arrestin-biased endomorphin-2 with the MOPr indicatedistinct receptor interactions and receptor conformations thatcould underlie their large differences in bias. Whereas bilorphinis systemically inactive, a glycosylated analog, bilactorphin, isorally active with similar in vivo potency to morphine. Bilorphinis both a unique molecular tool that enhances understanding ofMOPr biased signaling and a promising lead in the development ofnext generation analgesics.

Citation

Dekan, Z., Sianati, S., Yousuf, A., Sutcliffe, K. J., Gillis, A., Mallet, C., …Christie, M. J. (2019). A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor. Proceedings of the National Academy of Sciences, 116(44), 22353-22358. https://doi.org/10.1073/pnas.1908662116

• Journal Article Type: Article
• Acceptance Date: Sep 18, 2019
• Online Publication Date: Oct 14, 2019
• Publication Date: Oct 29, 2019
• Deposit Date: Sep 23, 2019
• Publicly Available Date: Oct 14, 2019
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 116
• Issue: 44
• Pages: 22353-22358
• DOI: https://doi.org/10.1073/pnas.1908662116
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/2648835
• Publisher URL: https://www.pnas.org/content/early/2019/10/08/1908662116