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

Research output: Contribution to journalArticle

Original languageEnglish
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Early online date14 Oct 2019
DOIs
DateAccepted/In press - 18 Sep 2019
DateE-pub ahead of print (current) - 14 Oct 2019

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.

    Research areas

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

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via National Academy of Sciences at https://www.pnas.org/content/early/2019/10/08/1908662116. Please refer to any applicable terms of use of the publisher.

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