Amide-to-chloroalkene substitution for overcoming intramolecular acyl transfer challenges in hexapeptidic neuromedin U receptor 2 agonists

Chem Commun (Camb). 2024 Mar 26;60(26):3563-3566. doi: 10.1039/d3cc06197c.

Abstract

CPN-116 is a peptidic agonist that activates human neuromedin U receptor type 2 (NMUR2) but suffers from chemical instability due to inherent backbone isomerization on the Dap residue. To address this, a Leu-Dap-type (Z)-chloroalkene dipeptide isostere was synthesized diastereoselectively as a surrogate of the Leu-Dap peptide bond to develop a (Z)-chloroalkene analogue of CPN-116. The synthesized CPN-116 analogue is stable in 1.0 M phosphate buffer (pH 7.4) without backbone isomerization and can activate NMUR2 with similar potency to CPN-116 at nM concentrations (EC50 = 1.0 nM).

MeSH terms

  • Amides / pharmacology
  • Humans
  • Neuropeptides* / chemistry
  • Peptides
  • Receptors, Neurotransmitter / agonists

Substances

  • neuromedin U receptor
  • Neuropeptides
  • Amides
  • Peptides
  • Receptors, Neurotransmitter