A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor.
Proc Natl Acad Sci U S A
; 116(44): 22353-22358, 2019 10 29.
Article
in En
| MEDLINE
| ID: mdl-31611414
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 ß-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oligopeptides
/
Penicillium
/
Fungal Proteins
/
Receptors, Opioid, mu
/
Analgesics, Opioid
Limits:
Animals
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2019
Document type:
Article
Affiliation country:
Australia