Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov;181(22):4677-4692.
doi: 10.1111/bph.17310. Epub 2024 Aug 18.

Biased receptor signalling and intracellular trafficking profiles of structurally distinct formylpeptide receptor 2 agonists

Cheng Peng  1 , Elizabeth A Vecchio  1 , Anh T N Nguyen  1 , Mia De Seram  1 , Ruby Tang  1 , Peter Keov  1 , Owen L Woodman  1 , Yung-Chih Chen  2 , Jonathan Baell  3 , Lauren T May  1 , Peishen Zhao  1 , Rebecca H Ritchie  1 , Cheng Xue Qin  1
Affiliations

Biased receptor signalling and intracellular trafficking profiles of structurally distinct formylpeptide receptor 2 agonists

Cheng Peng et al. Br J Pharmacol. 2024 Nov.

Abstract

Background: There is increasing interest in developing FPR2 agonists (compound 43, ACT-389949 and BMS-986235) as potential pro-resolving therapeutics, with ACT-389949 and BMS-986235 having entered phase I clinical development. FPR2 activation leads to diverse downstream outputs. ACT-389949 was observed to cause rapid tachyphylaxis, while BMS-986235 and compound 43 induced cardioprotective effects in preclinical models. We aim to characterise the differences in ligand-receptor engagement and downstream signalling and trafficking bias profile.

Experimental approach: Concentration-response curves to G protein dissociation, β-arrestin recruitment, receptor trafficking and second messenger signalling were generated using FPR2 ligands (BMS-986235, ACT-389949, compound 43 and WKYMVm), in HEK293A cells. Log(τ/KA) was obtained from the operational model for bias analysis using WKYMVm as a reference ligand. Docking of FPR2 ligands into the active FPR2 cryoEM structure (PDBID: 7T6S) was performed using ICM pro software.

Key results: Bias analysis revealed that WKYMVm and ACT-389949 shared a very similar bias profile. In comparison, BMS-986235 and compound 43 displayed approximately 5- to 50-fold bias away from β-arrestin recruitment and trafficking pathways, while being 35- to 60-fold biased towards cAMP inhibition and pERK1/2. Molecular docking predicted key amino acid interactions at the FPR2 shared between WKYMVm and ACT-389949, but not with BMS-986235 and compound 43.

Conclusion and implications: In vitro characterisation demonstrated that WKYMVm and ACT-389949 differ from BMS-986235 and compound 43 in their signalling and protein coupling profile. This observation may be explained by differences in the ligand-receptor interactions. In vitro characterisation provided significant insights into identifying the desired bias profile for FPR2-based pharmacotherapy.

Keywords: Aspirin triggered lipoxin A4; FPR2; internalisation; receptor trafficking; resolution of inflammation; β‐arrestin‐2.

PubMed Disclaimer

References

REFERENCES

    1. Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Abbracchio, M. P., Abraham, G., Agoulnik, A., Alexander, W., Al‐Hosaini, K., Bäck, M., Baker, J. G., Barnes, N. M., … Ye, R. D. (2023). The Concise Guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. British Journal of Pharmacology, 180, S23–S144. https://doi.org/10.1111/bph.16177
    1. Asahina, Y., Wurtz, N. R., Arakawa, K., Carson, N., Fujii, K., Fukuchi, K., Garcia, R., Hsu, M. Y., Ishiyama, J., Ito, B., Kick, E., Lupisella, J., Matsushima, S., Ohata, K., Ostrowski, J., Saito, Y., Tsuda, K., Villarreal, F., Yamada, H., … Kohno, Y. (2020). Discovery of BMS‐986235/LAR‐1219: A potent formyl peptide receptor 2 (FPR2) selective agonist for the prevention of heart failure. Journal of Medicinal Chemistry, 63, 9003–9019. https://doi.org/10.1021/acs.jmedchem.9b02101
    1. Aswanikumar, S., Corcoran, B., Schiffmann, E., Day, A. R., Freer, R. J., Showell, H. J., Becker, E. L., & Pert, C. B. (1977). Demonstration of a receptor on rabbit neutrophils for chemotactic peptides. Biochemical and Biophysical Research Communications, 74, 810–817. https://doi.org/10.1016/0006-291X(77)90375-8
    1. Badolato, R., Johnston, J. A., Wang, J. M., McVicar, D., Xu, L. L., Oppenheim, J. J., & Kelvin, D. J. (1995). Serum amyloid a induces calcium mobilization and chemotaxis of human monocytes by activating a pertussis toxin‐sensitive signaling pathway. Journal of Immunology, 155, 4004–4010. https://doi.org/10.4049/jimmunol.155.8.4004
    1. Bae, Y. S., Song, J. Y., Kim, Y., He, R., Ye, R. D., Kwak, J. Y., Suh, P. G., & Ryu, S. H. (2003). Differential activation of formyl peptide receptor signaling by peptide ligands. Molecular Pharmacology, 64, 841–847. https://doi.org/10.1124/mol.64.4.841

MeSH terms

LinkOut - more resources