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

Edin Muratspahić, Nataša Tomašević, Johannes Koehbach, Leopold Duerrauer, Seid Hadžić, Joel Castro, Gudrun Schober, Spyridon Sideromenos, Richard J. Clark, Stuart M. Brierley, David J. Craik, Christian W. Gruber

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)9042-9055
Number of pages14
JournalJournal of Medicinal Chemistry
Volume64
Issue number13
DOIs
Publication statusPublished - 8 Jul 2021

Keywords

  • opioid crisis
  • κ-opioid receptor (KOR)
  • Analgesics
  • Sunflower (Helianthus annuus)
  • sunflower for analgesic purposes
  • Helianthus annuus for analgesic purposes

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