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Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor.
Tomasevic, Natasa; Emser, Fabiola Susanna; Muratspahic, Edin; Gattringer, Jasmin; Hasinger, Simon; Hellinger, Roland; Keov, Peter; Felkl, Manuel; Gertsch, Jürg; Becker, Christian F W; Gruber, Christian W.
Afiliación
  • Tomasevic 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.
  • Muratspahic 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.
J Biol Chem ; 300(6): 107330, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38679329
ABSTRACT
The cannabinoid type 2 receptor (CB2R), a G protein-coupled receptor, is an important regulator of immune cell function and a promising target to treat chronic inflammation and fibrosis. While CB2R 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 CB2R. 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 CB2R 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 CB2R with an affinity (Ki) of 1 µM and a potency (EC50) of 8 µM. Leveraging deep learning networks, we verified the structural topology of vodo-C1 and modeled its molecular volume in comparison to the CB2R 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 CB2R. This study introduces a macrocyclic peptide phytocannabinoid, which served as a template for the development of synthetic CB2R peptide modulators. These findings offer opportunities for future peptide-based probe and drug development at cannabinoid receptors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor Cannabinoide CB2 Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Austria

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor Cannabinoide CB2 Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Austria
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