Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 44, Pages 22353-22358Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908662116
Keywords
biased agonist; mu-opioid receptor; peptide drug; opioid analgesic; glycosylation
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Funding
- National Health and Medical Research Council of Australia [APP1072113]
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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) mu-opioid agonists, which led to the design of bilorphin, a potent and selective mu-opioid receptor (MOPr) agonist (K-i 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit beta-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting beta-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.
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