Improving <em>in vivo</em> analgesia through glycosylation of bilorphin, a biased μ-opioid derived from a novel tetrapeptide class found in an Australian fungus  — ASN Events
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  3. Improving in vivo analgesia through glycosylation of bilorphin, a biased μ-opioid derived from a novel tetrapeptide class found in an Australian fungus 

Improving in vivo analgesia through glycosylation of bilorphin, a biased μ-opioid derived from a novel tetrapeptide class found in an Australian fungus  (#227)

Zoltan Dekan 1 , Setareh Sianati 2 , Arsalan Yousuf 2 , Katy J Sutcliffe 3 , Alexander Gillis 2 , Christian Mallet 2 4 , Paramjit Singh 1 , A H Jin 1 , Anna M Wang 2 , Sarasa A Mohammadi 2 , Michael Stewart 1 , Ranjala Ratnayake 1 , Frank Fontaine 1 , Earnest Lacey 5 , Andrew M Piggott 1 , Yan P Du 2 , Meritxell Canals 6 , Richard B Sessions 3 , Eamonn Kelly 3 , Robert J Capon 1 , Paul F Alewood 1 , MacDonald J Christie 2
  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
  2. Discipline of Pharmacology, University of Sydney, Camperdown, NSW, Australia
  3. Schools of Physiology, Pharmacology and Neuroscience, and Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol, UK
  4. INSERM, NEURO-DOL Basics & Clinical Pharmacology of Pain, Université Clermont Auvergne, Clermont-Ferrand, France
  5. Microbial Screening Technologies, Smithfield, NSW, Australia
  6. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

We present the discovery of three novel tetrapeptides (bilaids) from an Australian estuarine Penicillium species, and their subsequent development into a pharmacologically unique opioid analgesic (bilorphin). The bilaids structurally resemble known opioid agonist peptides but have an unusual stereochemical arrangement of amino acids (LDLD). We found that they were indeed weak μ-opioid agonists (Ki low mM). Building on the bilaid scaffold led us to create bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (Ki in nM: μ = 1.1, δ = 190, κ = 770). Importantly, bilorphin is a G-protein biased MOPr agonist that weakly phosphorylates the MOPr, marginally recruits β-arrestin, and produces no receptor internalization, in contrast to all previously characterized natural opioid peptides. Agonists of the MOPr that are functionally selective for G-protein signaling promise to produce fewer opioid related side effects compared to those that efficaciously recruit β-arrestin. However, bilorphin only produced analgesia in mice when administered intrathecally and was systemically inactive, indicating an inability to reach the CNS. We therefore developed a glycosylated analogue, bilactorphin, that was an effective analgesic in vivo through either subcutaneous, intravenous as well as oral administration. In addition to providing a novel pharmacological tool for exploring MOPr signaling, bilorphin is a stable scaffold for the development of orally active analgesics with potentially minimal adverse effects.