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

Abstract

SignificanceAgonists of the μ-opioid receptor (MOPr) are currently the gold standard for pain treatment. However, their therapeutic usage is greatly limited by side effects including respiratory depression, constipation, tolerance, and dependence. Functionally selective MOPr agonists that mediate their effects preferentially through G proteins rather than β-arrestin signaling are believed to produce fewer side effects. Here, we present the discovery of 3 unusual tetrapeptides with a unique stereochemical arrangement of hydrophobic amino acids from an Australian estuarine isolate of Penicillium species. Building on these natural templates we developed bilorphin, a potent and selective highly G protein-biased agonist of the MOPr. Further, through the addition of a simple sugar moiety, we generated bilactorphin that is an effective analgesic in vivo.

Intrinsic Efficacy of Opioid Ligands and Its Importance for Apparent Bias, Operational Analysis, and Therapeutic Window

“…1E). The window for detection of G protein-biased agonists is limited without increasing signal-to-noise ratio in a given arrestin assay, for instance by G protein receptor kinase overexpression (Dekan et al, 2019;Gillis et al, 2020). A high-efficacy agonist, such as DAMGO, is the most appropriate reference compound in studies of the MOR because it is the most likely to define the maximum possible effect in most assays.…”

“…If rank order of ligand maximal effect, when signal windows are not limited, and potency are conserved between assays, true ligand bias is unlikely to be present regardless of how amplification alters operational parameters. Notably, when these confounds are addressed, endomorphin 2 has been consistently observed to be arrestin-biased when compared with met-enkephalin (Rivero et al, 2012;Dekan et al, 2019), and a peptidergic agonist appears to have lower efficacy for arrestin recruitment than would be predicted from G protein-efficacy estimates (Dekan et al, 2019).…”

Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1

“…Although mechanisms underlying morphine-mediated processes remain the subject of much debate, morphine stimulation activates G protein-coupled opioid receptors and then induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, and activation of potassium channels (Qu et al, 2017;Yang et al, 2019). In addition, other signalling pathways, including mitogenactivated kinases (MAPK), b-arrestin, phospholipase C, protein kinase, PI3K, and extracellular signal-regulated kinase (ERK) pathways, are also involved in morphine activity (Bianchi et al, 2010;Zhang and Pan, 2010;Dai et al, 2018;Shen et al, 2018;de Freitas et al, 2019;Dekan et al, 2019;Listos et al, 2019). Recently, the role of oxidative stress in morphine action has been paid more attention.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…Further, compounds derived from natural resources are valuable leads for new drug candidates. Both strategies have been combined by Dekan et al [39], where discovery of three unusual tetrapeptides with a unique stereochemical arrangement of hydrophobic amino acids from an Australian estuarine isolate of Penicillium species is presented. The SAR study led to the design of bilorphin ( Figure 5), a potent and selective G protein-biased MOPr agonist.…”