Development of a Selective Peptide κ-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples

J Med Chem. 2023 Sep 14;66(17):11843-11854. doi: 10.1021/acs.jmedchem.3c00426. Epub 2023 Aug 26.

Abstract

The κ-opioid receptor (KOR) is an attractive target for the development of novel drugs. KOR agonists are potentially safer pain medications, whereas KOR antagonists are promising drug candidates for the treatment of neuropsychiatric disorders. Hitherto, the vast majority of selective drug leads that have been developed for KOR are small molecules. In this study, novel peptide probes were designed by using an endogenous dynorphin A1-13 sequence as a template for peptide stapling via late-stage cysteine functionalization. Leveraging this strategy, we developed a stable and potent KOR antagonist, CSD-CH2(1,8)-NH2, with approximately 1000-fold improved selectivity for KOR over μ- and δ-opioid receptors. Its potent competitive KOR antagonism was verified in KOR-expressing cells, peripheral dorsal root ganglion neurons, and using the tail-flick and rotarod tests in mice. This work highlights the value of cysteine stapling to develop selective peptide probes to modulate central KOR function, as innovative peptide drug candidates for the treatment of KOR-related illnesses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cysteine*
  • Dynorphins
  • Ganglia, Spinal
  • Mice
  • Narcotic Antagonists*
  • Peptides / pharmacology
  • Receptors, Opioid, kappa

Substances

  • Narcotic Antagonists
  • Cysteine
  • Peptides
  • Dynorphins
  • Receptors, Opioid, kappa