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

Jürgen Einsiedel; Maximilian F Schmidt; Harald Hübner; Peter Gmeiner

doi:10.1016/j.bmc.2022.116720

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. Epub 2022 Mar 19.

Authors

Jürgen Einsiedel¹, Maximilian F Schmidt¹, Harald Hübner¹, Peter Gmeiner²

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: peter.gmeiner@fau.de.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Disulfides*
Homocysteine
Neurotensin*
Peptides / pharmacology
Receptors, Neurotensin / agonists

Substances

Disulfides
Peptides
Receptors, Neurotensin
Homocysteine
Neurotensin