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)μ-opioid agonists, which led to the design of bilorphin, a potent andselectiveμ-opioid receptor (MOPr) agonist (Ki1.1 nM). In sharp con-trast to all-natural product opioid peptides that efficaciously recruitβ-arrestin, bilorphin is G protein biased, weakly phosphorylatingthe MOPr and marginally recruitingβ-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., Singh, P., Jin, A. H., Wang, A. M., Mohammadi, S. A., Stewart, M., Ratnayake, R., Fontaine, F., Lacey, E., Piggott, A. M., Du, Y. P., Canals, M., Sessions, R. B., Kelly, E. .., Capon, R. J., …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
• Contract Date: Sep 23, 2019