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, Rebecca H. Ritchie

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number14232
Number of pages13
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 7 Feb 2017

Keywords

  • heart failure
  • receptor pharmacology

Cite this

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title = "Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice",
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.",
keywords = "heart failure, receptor pharmacology",
author = "Qin, {Cheng Xue} and May, {Lauren T.} and Renming Li and Nga Cao and Sarah Rosli and Minh Deo and Alexander, {Amy E} and Duncan Horlock and Bourke, {Jane E.} and Yang, {Yuan H.} and Stewart, {Alastair G.} and Kaye, {David M.} and Du, {Xiao Jun} and Sexton, {Patrick M.} and Arthur Christopoulos and Gao, {Xiao Ming} and Ritchie, {Rebecca H.}",
year = "2017",
month = "2",
day = "7",
doi = "10.1038/ncomms14232",
language = "English",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice. / Qin, Cheng Xue; May, Lauren T.; Li, Renming; Cao, Nga; Rosli, Sarah; Deo, Minh; Alexander, Amy E; Horlock, Duncan; Bourke, Jane E.; Yang, Yuan H.; Stewart, Alastair G.; Kaye, David M.; Du, Xiao Jun; Sexton, Patrick M.; Christopoulos, Arthur; Gao, Xiao Ming; Ritchie, Rebecca H.

In: Nature Communications, Vol. 8, 14232, 07.02.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice

AU - Qin, Cheng Xue

AU - May, Lauren T.

AU - Li, Renming

AU - Cao, Nga

AU - Rosli, Sarah

AU - Deo, Minh

AU - Alexander, Amy E

AU - Horlock, Duncan

AU - Bourke, Jane E.

AU - Yang, Yuan H.

AU - Stewart, Alastair G.

AU - Kaye, David M.

AU - Du, Xiao Jun

AU - Sexton, Patrick M.

AU - Christopoulos, Arthur

AU - Gao, Xiao Ming

AU - Ritchie, Rebecca H.

PY - 2017/2/7

Y1 - 2017/2/7

N2 - 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.

AB - 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.

KW - heart failure

KW - receptor pharmacology

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U2 - 10.1038/ncomms14232

DO - 10.1038/ncomms14232

M3 - Article

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 14232

ER -