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Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice

Author

Listed:
  • Cheng Xue Qin

    (Baker IDI Heart and Diabetes Institute
    University of Melbourne)

  • Lauren T. May

    (Monash University)

  • Renming Li

    (Baker IDI Heart and Diabetes Institute
    University of Melbourne)

  • Nga Cao

    (Baker IDI Heart and Diabetes Institute)

  • Sarah Rosli

    (Baker IDI Heart and Diabetes Institute)

  • Minh Deo

    (Baker IDI Heart and Diabetes Institute)

  • Amy E. Alexander

    (Baker IDI Heart and Diabetes Institute)

  • Duncan Horlock

    (Baker IDI Heart and Diabetes Institute)

  • Jane E. Bourke

    (Monash University)

  • Yuan H. Yang

    (Centre of Inflammatory Diseases, Monash University)

  • Alastair G. Stewart

    (University of Melbourne)

  • David M. Kaye

    (Baker IDI Heart and Diabetes Institute)

  • Xiao-Jun Du

    (Baker IDI Heart and Diabetes Institute)

  • Patrick M. Sexton

    (Monash University)

  • Arthur Christopoulos

    (Monash University)

  • Xiao-Ming Gao

    (Baker IDI Heart and Diabetes Institute)

  • Rebecca H. Ritchie

    (Baker IDI Heart and Diabetes Institute
    University of Melbourne
    Monash University)

Abstract

Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43. The pathological importance of the biased agonism of Cmpd17b is demonstrable as superior cardioprotection in both in vitro (cardiomyocytes and cardiofibroblasts) and MI injury in mice in vivo. These findings reveal new insights for development of small molecule FPR agonists with an improved cardioprotective profile for treating MI.

Suggested Citation

  • Cheng Xue Qin & Lauren T. May & Renming Li & Nga Cao & Sarah Rosli & Minh Deo & Amy E. Alexander & Duncan Horlock & Jane E. Bourke & Yuan H. Yang & Alastair G. Stewart & David M. Kaye & Xiao-Jun Du & , 2017. "Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14232
    DOI: 10.1038/ncomms14232
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    Cited by:

    1. Geng Chen & Xiankun Wang & Qiwen Liao & Yunjun Ge & Haizhan Jiao & Qiang Chen & Yezhou Liu & Wenping Lyu & Lizhe Zhu & Gydo C. P. Zundert & Michael J. Robertson & Georgios Skiniotis & Yang Du & Hongli, 2022. "Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Jennifer A. E. Payne & Julien Tailhades & Felix Ellett & Xenia Kostoulias & Alex J. Fulcher & Ting Fu & Ryan Leung & Stephanie Louch & Amy Tran & Severin A. Weber & Ralf B. Schittenhelm & Graham J. Li, 2021. "Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Youwen Zhuang & Lei Wang & Jia Guo & Dapeng Sun & Yue Wang & Weiyi Liu & H. Eric Xu & Cheng Zhang, 2022. "Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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