Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor.

Autor: Tomašević N; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Emser FS; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Muratspahić E; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Gattringer J; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Hasinger S; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Hellinger R; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria., Keov P; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Felkl M; Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria., Gertsch J; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland., Becker CFW; Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria., Gruber CW; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: christian.w.gruber@meduniwien.ac.at.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2024 Jun; Vol. 300 (6), pp. 107330. Date of Electronic Publication: 2024 Apr 26.
DOI: 10.1016/j.jbc.2024.107330
Abstrakt: The cannabinoid type 2 receptor (CB 2 R), a G protein-coupled receptor, is an important regulator of immune cell function and a promising target to treat chronic inflammation and fibrosis. While CB 2 R is typically targeted by small molecules, including endo-, phyto-, and synthetic cannabinoids, peptides-owing to their size-may offer a different interaction space to facilitate differential interactions with the receptor. Here, we explore plant-derived cyclic cystine-knot peptides as ligands of the CB 2 R. Cyclotides are known for their exceptional biochemical stability. Recently, they gained attention as G protein-coupled receptor modulators and as templates for designing peptide ligands with improved pharmacokinetic properties over linear peptides. Cyclotide-based ligands for CB 2 R were profiled based on a peptide-enriched extract library comprising nine plants. Employing pharmacology-guided fractionation and peptidomics, we identified the cyclotide vodo-C1 from sweet violet (Viola odorata) as a full agonist of CB 2 R with an affinity (K i ) of 1 μM and a potency (EC 50 ) of 8 μM. Leveraging deep learning networks, we verified the structural topology of vodo-C1 and modeled its molecular volume in comparison to the CB 2 R ligand binding pocket. In a fragment-based approach, we designed and characterized vodo-C1-based bicyclic peptides (vBCL1-4), aiming to reduce size and improve potency. Opposite to vodo-C1, the vBCL peptides lacked the ability to activate the receptor but acted as negative allosteric modulators or neutral antagonists of CB 2 R. This study introduces a macrocyclic peptide phytocannabinoid, which served as a template for the development of synthetic CB 2 R peptide modulators. These findings offer opportunities for future peptide-based probe and drug development at cannabinoid receptors.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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