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

Zoltan Dekan, Setareh Sianati, Arsalan Yousuf, Katy Sutcliffe, Alexander Gillis, Christopher Mallet, Paramijt Singh, Aihue Jin, Anna Wang, Sarasa Mohammadi, Michael Stewart, Ranjala Ratnayake, Frank Fontaine, Ernest Lacey, Andrew Piggott, Yan Du, Meritxell Canals, Richard B Sessions, Eamonn P Kelly, Robert CaponPaul Alewood, Macdonald J Christie

Research output: Contribution to journalArticle (Academic Journal)

8 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)22353-22358
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number44
Early online date14 Oct 2019
DOIs
Publication statusPublished - 29 Oct 2019

Keywords

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

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