Researchers from the University of Queensland and the University of Sydney have discovered a new class of peptides with unusual alternating chirality from which a novel analgesic was derived (Dekan Z., Sianati S., Yousuf A., Sutcliffe K.J., Gillis A., Mallet C., Singh P., Jin A.H., Wang A.M., Mohammadi S.A., Stewart M., Ratnayake R., Fontaine F., Lacey E., Piggott A.M., Du Y.P., Canals M., Sessions R.B., Kelly E., Capon R.J., Alewood P.F., Christie M.J. Proc. Natl Acad. Sci. USA 2019, 116, 22 353–8). The peptides, called bilaids, were isolated from a Penicillium species. Given their resemblance to known short peptide opioid agonists, the researchers modified them, leading to the design of bilorphin, a potent and selective mu-opioid receptor agonist. In sharp contrast to all natural product opioid peptides, which efficaciously recruit β-arrestin, bilorphin is G-protein biased, only marginally recruiting β-arrestin, with no receptor internalisation. Molecular dynamics simulations of bilorphin suggested that distinct receptor interactions may underlie its biased pharmacology. Further modifications to bilorphin led to a glycosylated analogue, bilactorphin, which is orally active with similar in vivo potency to morphine.