Development of disulfide-functionalized peptides covalently binding G protein-coupled receptors

  • Bioorg Med Chem. 2022 May 1:61:116720. doi: 10.1016/j.bmc.2022.116720.
Jürgen Einsiedel  1 ,  Maximilian F Schmidt  1 ,  Harald Hübner  1 ,  Peter Gmeiner  2
Affiliations
  • 1. Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, D-91058 Erlangen, Germany.
  • 2. Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, D-91058 Erlangen, Germany. Electronic address: [email protected].
PMID: 35334449 DOI: 10.1016/j.bmc.2022.116720
Abstract

A broadly applicable synthesis of peptides incorporating mixed disulfides between cysteine and homocysteine and cysteamine was developed. The method was established using pharmacologically relevant G protein-coupled receptor (GPCR) ligands including the μ-receptor agonist Dmt-DALDA and extended to the orexin derivative Oxa(17-33) and NT(8-13), the C-terminal hexapeptide of neurotensin. The newly developed NT(8-13) analog 6b incorporating an S-functionalized homocysteine revealed covalent binding of the Neurotensin Receptor 1 (NTSR1) in a radioligand depletion study.

Keywords
Covalent ligand; Disulfide tethering; G protein-coupled receptor; Neurotensin receptor.
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