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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.


Zoltan Dekan

Setareh Sianati

Arsalan Yousuf

Katy J. Sutcliffe

Alexander Gillis

Christian Mallet

Paramjit Singh

Aihua H. Jin

Anna M. Wang

Sarasa A. Mohammadi

Michael Stewart

Ranjala Ratnayake

Frank Fontaine

Earnest Lacey

Andrew M. Piggott

Yan P. Du

Richard B. Sessions

Eamonn . Kelly

Robert J. Capon

Paul F. Alewood

MacDonald J. Christie


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.


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.

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
Keywords Multidisciplinary
Public URL
Publisher URL


Supplementary information: Biased ?-opioid analgesics derived from a novel tetrapeptide class found in an Australian fungus (1.7 Mb)

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