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

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

  • Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22353-22358. doi: 10.1073/pnas.1908662116.
Zoltan Dekan 1,  Setareh Sianati 2,  Arsalan Yousuf 2,  Katy J Sutcliffe 3,  Alexander Gillis 2,  Christophe Mallet 2,  Paramjit Singh 1,  Aihua H Jin 1,  Anna M Wang 2,  Sarasa A Mohammadi 2,  Michael Stewart 1,  Ranjala Ratnayake 1,  Frank Fontaine 1,  Ernest Lacey 4,  Andrew M Piggott 1,  Yan P Du 2,  Meritxell Canals 5,  Richard B Sessions 3,  Eamonn Kelly 3,  Robert J Capon 6,  Paul F Alewood 6,  MacDonald J Christie 7
Affiliations

Affiliations

  • 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.
PMID: 31611414 DOI: 10.1073/pnas.1908662116
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 (Ki low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (Ki 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.

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