Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice.
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.
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.|Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia.
Cheng Xue
CX
Qin
Department of Pharmacology, Division of Drug Discovery Biology, Department of Pharmacology, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Lauren T
LT
May
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.|Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia.
Renming
R
Li
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Nga
N
Cao
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Sarah
S
Rosli
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Minh
M
Deo
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Amy E
AE
Alexander
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Duncan
D
Horlock
Department of Pharmacology, Monash University, Wellington Road and Blackburn Road, Clayton, Victoria 3800, Australia.
Jane E
JE
Bourke
Centre of Inflammatory Diseases, Monash University, Clayton, Victoria 3168, Australia.
Yuan H
YH
Yang
Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia.
Alastair G
AG
Stewart
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
David M
DM
Kaye
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Xiao-Jun
XJ
Du
Department of Pharmacology, Division of Drug Discovery Biology, Department of Pharmacology, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Patrick M
PM
Sexton
Department of Pharmacology, Division of Drug Discovery Biology, Department of Pharmacology, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Arthur
A
Christopoulos
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.
Xiao-Ming
XM
Gao
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria 3004, Australia.|Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia.|Department of Medicine, Monash University, Parkville, Victoria 3800, Australia.
Rebecca H
RH
Ritchie
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003412:Cricetulus; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D002316:Cardiotonic Agents; C469986:FPR1 protein, human; C105101:FPR2 protein, human; D011724:Pyridazines; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium