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

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, Patrick M. Sexton, Arthur Christopoulos, Xiao-Ming Gao and Rebecca H. Ritchie ()
Additional contact information
Cheng Xue Qin: Baker IDI Heart and Diabetes Institute
Lauren T. May: Monash University
Renming Li: Baker IDI Heart and Diabetes Institute
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

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14232

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