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Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22353-22358. doi: 10.1073/pnas.1908662116. Epub 2019 Oct 14.

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

Author information

1
Institute for Molecular Bioscience, The University of Queensland, 4072 Brisbane, Australia.
2
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia.
3
Schools of Physiology, Pharmacology and Neuroscience, and Biochemistry, Biomedical Sciences Building, University of Bristol, BS8 1TD Bristol, United Kingdom.
4
Microbial Screening Technologies Pty. Ltd., Smithfield, NSW, 2164, Australia.
5
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, 3052 Parkville, Australia.
6
Institute for Molecular Bioscience, The University of Queensland, 4072 Brisbane, Australia; r.capon@imb.uq.edu.au p.alewood@imb.uq.edu.au mac.christie@sydney.edu.au.
7
Discipline of Pharmacology, School of Medical Sciences, University of Sydney, NSW 2006, Australia; r.capon@imb.uq.edu.au p.alewood@imb.uq.edu.au mac.christie@sydney.edu.au.

Abstract

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (K i low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (K i 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.

KEYWORDS:

biased agonist; glycosylation; opioid analgesic; peptide drug; μ-opioid receptor

Conflict of interest statement

Competing interest statement: Patent Application(s) corresponding to Australian Patent Application 2018901944 The University of Sydney and The University of Queensland has been filed concerning this peptide. Title: Analgesics and Methods of Use Thereof.

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