(491.17) The Design of an Antagonist that Improves Cardiac Function through Ligand-Directed Signaling

Poster Board Number: A125

Karthik Pittala (University of Michigan Medical School ), Ruthann Nichols (University of Michigan Medical School ), Benjamin Maynard (University of Michigan Medical School ), Megan Leander (University of Michigan Medical School ), Jeff Creech (University of Michigan Center for Arrhythmia Research), Andre Monteria da Rocha (University of Michigan Center for Arrhythmia Research), Todd Heron (University of Michigan Center for Arrhythmia Research)

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.