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.

Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing

“…We detected a very strong positive monotonic correlation between EC 50 values for cAMP inhibition and ERK phosphorylation (r = 0.933, p = 0.001, n 9). A similar trend could also be established for the corresponding E max values, which again revealed a strong positive correlation (0.733, p = 0.031, n 9; for an overview of logEC 50 and E maxA values, see Figure A4 and Table A2.). To directly assess whether the different molecular pathways are driven by Gα i -protein-dependent signal transduction, we repeated our experiments in the presence of the Gα i -specific inhibitor pertussis toxin (PTX) at a concentration that completely abolished the inhibition of cAMP formation induced by W-peptide ( Figure A4a).…”

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

“…Indeed, administration of human recombinant ANXA1 halted further decline in cardiac function in diabetic mice via a pathway that included the restoration of Akt signalling 135. Targeting strategies have additionally included the use of ANXA1 peptides136 and small‐molecule‐biased formyl peptide receptor agonists to protect against myocardial injury 137. Recent data have shown, albeit not in a diabetic context, that myocardial dysfunction postischaemia is prevented by endogenous annexin‐A1 and an N‐terminal‐derived peptide Ac‐ANX‐A1(2‐26) 138.…”

“…135 Targeting strategies have additionally included the use of ANXA1 peptides 136 and small-moleculebiased formyl peptide receptor agonists to protect against myocardial injury. 137 Recent data have shown, albeit not in a diabetic context, that myocardial dysfunction postischaemia is prevented by endogenous annexin-A1 and an N-terminal-derived peptide Ac-ANX-A1 . 138 The antiinflammatory properties of annexin-1 peptides have been largely ascribed to their powerful antineutrophil actions in vivo.…”

Decoding the chemotactic signal

“…Biased signaling is widespread in the chemokine system, with different chemokine ligands eliciting unique signaling profiles at the same receptor . While much less established, biased signaling may also play a role in the formylated peptide receptor system . Although biased signaling has not been explicitly described in D. discoideum , D. discoideum nevertheless has numerous cytosolic effectors available to initiate complex signaling outcomes that are adaptable in different environmental circumstances .…”

“…106 While much less established, biased signaling may also play a role in the formylated peptide receptor system. 98,99,[135][136][137] Although biased signaling has not been explicitly 139 Importantly, other recent studies suggest that differences in chemokine-receptor interactions far from the traditional receptor binding pocket influence how a single receptor can mediate alternative functional responses. 140,141 In one example, CXCL12 provokes and arrests chemotaxis in a monomeric and dimeric form, respectively, and structures of CXCL12 bound to its receptor CXCR4 in both forms demonstrate mutually exclusive interactions that may influence CXCL12's opposing effects on chemotaxis.…”