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 J.
AU - Gillis, Alexander
AU - Mallet, Christophe
AU - Singh, Paramjit
AU - Jin, Aihua H.
AU - Wang, Anna M.
AU - Mohammadi, Sarasa A.
AU - Stewart, Michael
AU - Ratnayake, Ranjala
AU - Fontaine, Frank
AU - Lacey, Ernest
AU - Piggott, Andrew M.
AU - Du, Yan P.
AU - Canals, Meritxell
AU - Sessions, Richard B.
AU - Kelly, Eamonn
AU - Capon, Robert J.
AU - Alewood, Paul F.
AU - Christie, MacDonald J.
N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2019/10/29
Y1 - 2019/10/29
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
UR - http://www.scopus.com/inward/record.url?scp=85074216180&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/1072113
U2 - 10.1073/pnas.1908662116
DO - 10.1073/pnas.1908662116
M3 - Article
C2 - 31611414
AN - SCOPUS:85074216180
VL - 116
SP - 22353
EP - 22358
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
IS - 44
ER -