De novo macrocyclic peptide discovery produces potent class A GPCR ligands with diverse pharmacology
- 1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
Abstract
G protein-coupled receptors (GPCRs) represent one of the largest protein families of therapeutic importance, as over one third of all currently approved drugs target GPCRs. A growing proportion of GPCR drugs are peptides. However, class A GPCRs (over 80% of clinically studied targets) are underexploited as peptide targets, presumably since their only structured domain is the core, seven-helix, integral membrane fold presenting a limited solvent-exposed surface area. Screening libraries of de novo macrocyclic peptides have allowed for the targeting of otherwise intractable proteins, but their potential to generate selective ligands for class A GPCRs has not been demonstrated. Here, we used random nonstandard peptides integrated discovery (RaPID) to identify de novo macrocyclic peptide ligands targeting the chemokine receptor CXCR4. CXCR4 regulates cell migration, immune surveillance, and inflammation, making it an important therapeutic target for multiple diseases. We discovered novel, potent CXCR4-selective antagonists binding within the orthosteric pocket with nanomolar affinity. The most active peptides effectively inhibited receptor signaling, suppressed chemokine-driven cell migration, and blocked CXCR4-driven HIV entry. Our results show that even the structurally minimal class A GPCRs are viable targets for de novo cyclic peptide discovery, highlighting the potential for uncovering ligands towards other members of the GPCR superfamily.
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BibTeX
@misc{salgadopolo2026novo,
title = {{De novo macrocyclic peptide discovery produces potent class A GPCR ligands with diverse pharmacology}},
author = {F. Salgado-Polo and M. Matic and P. B. Rainsford and F. Faas and M. Meyrath and R. Regmi and M. M. Rosenkilde and M. Szpakowska and A. Chevigne and A. S. Hauser and J. M. Rogers and M. Gustavsson},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760615},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760615v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - De novo macrocyclic peptide discovery produces potent class A GPCR ligands with diverse pharmacology
AU - F. Salgado-Polo
AU - M. Matic
AU - P. B. Rainsford
AU - F. Faas
AU - M. Meyrath
AU - R. Regmi
AU - M. M. Rosenkilde
AU - M. Szpakowska
AU - A. Chevigne
AU - A. S. Hauser
AU - J. M. Rogers
AU - M. Gustavsson
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760615
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760615v1
AB - G protein-coupled receptors (GPCRs) represent one of the largest protein families of therapeutic importance, as over one third of all currently approved drugs target GPCRs. A growing proportion of GPCR drugs are peptides. However, class A GPCRs (over 80% of clinically studied targets) are underexploited as peptide targets, presumably since their only structured domain is the core, seven-helix, integral membrane fold presenting a limited solvent-exposed surface area. Screening libraries of de novo macrocyclic peptides have allowed for the targeting of otherwise intractable proteins, but their potential to generate selective ligands for class A GPCRs has not been demonstrated. Here, we used random nonstandard peptides integrated discovery (RaPID) to identify de novo macrocyclic peptide ligands targeting the chemokine receptor CXCR4. CXCR4 regulates cell migration, immune surveillance, and inflammation, making it an important therapeutic target for multiple diseases. We discovered novel, potent CXCR4-selective antagonists binding within the orthosteric pocket with nanomolar affinity. The most active peptides effectively inhibited receptor signaling, suppressed chemokine-driven cell migration, and blocked CXCR4-driven HIV entry. Our results show that even the structurally minimal class A GPCRs are viable targets for de novo cyclic peptide discovery, highlighting the potential for uncovering ligands towards other members of the GPCR superfamily.
ER -