The Design of an Antagonist that Improves Cardiac Function through Ligand‐Directed Signaling

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The signaling pathway of a peptide that impacts cardiovascular physiology may be targeted to influence cardiac function. Through previous studies, we discovered that human RFRP‐1 (RFamide‐related peptide‐1; MPHSFANLPLRF‐NH2) decreases cardiac contractility. The structure and activity of RFRP‐1 are conserved across phylogeny, suggesting it plays a role in physiology. We determined RFRP‐1 structure‐activity relationship (SAR) in cardiomyocytes and demonstrated that it acts through RFRP‐1R, a G protein‐coupled receptor (GPCR). Based on RFRP‐1 SAR data, we designed LPLAF‐NH2 and found that it acts as a RFRP‐1R antagonist in cardiomyocytes and in animals. The alanyl‐substituted analog diminished the effects of the full‐length peptide and active core, but not at equimolar concentrations; the antagonist was less effective. In order to design a better antagonist, we turned to molecular docking software to investigate ligand‐receptor binding. As a result, we designed an antagonist with increased receptor interactions that improved cardiac function in human cardiomyocytes and consistent with ligand‐directed RFRP‐1R signaling.