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

Tomašević, Nataša; Emser, Fabiola Susanna; Muratspahić, Edin; Gattringer, Jasmin; Hasinger, Simon; Hellinger, Roland; Keov, Peter; Felkl, Manuel; Gertsch, Jürg; Becker, Christian F W; Gruber, Christian W (2024). Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor. The journal of biological chemistry, 300(6), p. 107330. American Society for Biochemistry and Molecular Biology 10.1016/j.jbc.2024.107330

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The cannabinoid-type 2 receptor (CB2R), a G protein-coupled receptor (GPCR), 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 GPCR 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 cyclotide vodo-C1 from sweet violet (Viola odorata) as a full agonist of CB2R with an affinity (Ki) of 1μM and a potency (EC50) of 8μM. Leveraging deep learning networks we verified the structural topology of vodo-C1 and modelled 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 template for the development of synthetic CB2R peptide modulators. These findings offer opportunities for future peptide-based probe and drug development at cannabinoid receptors.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1083-351X

Publisher:

American Society for Biochemistry and Molecular Biology

Language:

English

Submitter:

Pubmed Import

Date Deposited:

30 Apr 2024 13:03

Last Modified:

03 Jul 2024 00:14

Publisher DOI:

10.1016/j.jbc.2024.107330

PubMed ID:

38679329

Uncontrolled Keywords:

G protein-coupled receptor allosteric modulator cannabinoid type 2 receptor peptide plant

BORIS DOI:

10.48350/196342

URI:

https://boris.unibe.ch/id/eprint/196342

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