2. Academic Validation
  3. Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain

Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain

  • J Med Chem. 2021 Jul 8;64(13):9042-9055. doi: 10.1021/acs.jmedchem.1c00158.
Edin Muratspahić 1,  Nataša Tomašević 1,  Johannes Koehbach 2,  Leopold Duerrauer 1 3,  Seid Hadžić 1,  Joel Castro 4 5,  Gudrun Schober 4 5,  Spyridon Sideromenos 6,  Richard J Clark 3,  Stuart M Brierley 4 5 7,  David J Craik 2,  Christian W Gruber 1
Affiliations

Affiliations

  • 1 Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
  • 2 Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 3 School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 4 Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, South Australia 5042, Australia.
  • 5 Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
  • 6 Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, 1090 Vienna, Austria.
  • 7 Discipline of Medicine, University of Adelaide, North Terrace, Adelaide, South Australia 5000, Australia.
PMID: 34162205 DOI: 10.1021/acs.jmedchem.1c00158
Abstract

The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower (Helianthus annuus) preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic Peptides from Plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.

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