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

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A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor. / Dekan, Zoltan; Sianati, Setareh; Yousuf, Arsalan; Sutcliffe, Katy; Gillis, Alexander ; Mallet, Christopher ; Singh, Paramijt; Jin, Aihue; Wang, Anna ; Mohammadi, Sarasa; Stewart, Michael ; Ratnayake, Ranjala; Fontaine, Frank; Lacey, Ernest; Piggott, Andrew; Du, Yan; Canals, Meritxell; Sessions, Richard B; Kelly, Eamonn P; Capon, Robert; Alewood, Paul; Christie, Macdonald J.

In: Proceedings of the National Academy of Sciences of the United States of America, 14.10.2019.

Research output: Contribution to journalArticle

Harvard

Dekan, Z, Sianati, S, Yousuf, A, Sutcliffe, K, Gillis, A, Mallet, C, Singh, P, Jin, A, Wang, A, Mohammadi, S, Stewart, M, Ratnayake, R, Fontaine, F, Lacey, E, Piggott, A, Du, Y, Canals, M, Sessions, RB, Kelly, EP, Capon, R, Alewood, P & Christie, MJ 2019, 'A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor', Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1908662116

APA

Dekan, Z., Sianati, S., Yousuf, A., Sutcliffe, K., Gillis, A., Mallet, C., ... Christie, M. J. (2019). A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1908662116

Vancouver

Dekan Z, Sianati S, Yousuf A, Sutcliffe K, Gillis A, Mallet C et al. A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor. Proceedings of the National Academy of Sciences of the United States of America. 2019 Oct 14. https://doi.org/10.1073/pnas.1908662116

Author

Dekan, Zoltan ; Sianati, Setareh ; Yousuf, Arsalan ; Sutcliffe, Katy ; Gillis, Alexander ; Mallet, Christopher ; Singh, Paramijt ; Jin, Aihue ; Wang, Anna ; Mohammadi, Sarasa ; Stewart, Michael ; Ratnayake, Ranjala ; Fontaine, Frank ; Lacey, Ernest ; Piggott, Andrew ; Du, Yan ; Canals, Meritxell ; Sessions, Richard B ; Kelly, Eamonn P ; Capon, Robert ; Alewood, Paul ; Christie, Macdonald J. / A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2019.

Bibtex

@article{0dcc200d34274e6585db3cb64a7d2e9a,
title = "A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor",
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, μ-opioid receptor, peptide drug, opioid analgesic, glycosylation",
author = "Zoltan Dekan and Setareh Sianati and Arsalan Yousuf and Katy Sutcliffe and Alexander Gillis and Christopher Mallet and Paramijt Singh and Aihue Jin and Anna Wang and Sarasa Mohammadi and Michael Stewart and Ranjala Ratnayake and Frank Fontaine and Ernest Lacey and Andrew Piggott and Yan Du and Meritxell Canals and Sessions, {Richard B} and Kelly, {Eamonn P} and Robert Capon and Paul Alewood and Christie, {Macdonald J}",
year = "2019",
month = "10",
day = "14",
doi = "10.1073/pnas.1908662116",
language = "English",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor

AU - Dekan, Zoltan

AU - Sianati, Setareh

AU - Yousuf, Arsalan

AU - Sutcliffe, Katy

AU - Gillis, Alexander

AU - Mallet, Christopher

AU - Singh, Paramijt

AU - Jin, Aihue

AU - Wang, Anna

AU - Mohammadi, Sarasa

AU - Stewart, Michael

AU - Ratnayake, Ranjala

AU - Fontaine, Frank

AU - Lacey, Ernest

AU - Piggott, Andrew

AU - Du, Yan

AU - Canals, Meritxell

AU - Sessions, Richard B

AU - Kelly, Eamonn P

AU - Capon, Robert

AU - Alewood, Paul

AU - Christie, Macdonald J

PY - 2019/10/14

Y1 - 2019/10/14

N2 - 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.

AB - 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.

KW - biased agonist

KW - μ-opioid receptor

KW - peptide drug

KW - opioid analgesic

KW - glycosylation

U2 - 10.1073/pnas.1908662116

DO - 10.1073/pnas.1908662116

M3 - Article

C2 - 31611414

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

ER -