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

摘要: 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 which led design bilorphin, a potent and selective receptor (MOPr) agonist 1.1 nM). In sharp contrast all-natural product peptides efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating MOPr marginally recruiting no internalization. Importantly, exhibits similar bias oliceridine, small nonpeptide improved overdose safety. Molecular dynamics simulations strongly arrestin-biased endomorphin-2 indicate distinct interactions conformations could underlie large differences in bias. Whereas systemically inactive, glycosylated analog, bilactorphin, orally active vivo potency morphine. Bilorphin both unique molecular tool enhances understanding biased signaling promising lead development next generation analgesics.