Abstract 15212: Npa7, a First in Class Dual Receptor Activator With Renoprotective Properties
Introduction: Acute decompensated heart failure (ADHF) is a disease with high morbidity and mortality. Available treatment of ADHF oftentimes induces cardiorenal syndrome (CRS), which is a strong predictor of mortality, and warrants innovative drugs with novel modes of action as well as cardio-renoprotective properties. We used an innovative strategy to engineer a novel multivalent peptide (NPA7), which is a fusion of a 22 amino acid sequence of a pGC-A receptor (pGC-A) activator, and the Mas receptor (MasR) agonist ANG1-7 that possess complementary cardio-renoprotective properties. We hypothesized that NPA7 is a dual receptor activator in vitro with renoprotective properties in an experimental model of HF in vivo.
Methods and Results: First, we successfully synthesized NPA7 by solid phase peptide synthesis. Second, we confirmed in vitro binding of NPA7 to pGCA (green) and MasR (red), selectively overexpressed in HEK293 cells (GCA++ and Mas++, respectively) (figure 1A-B). We then assessed in vitro dual receptor activation using second messengers cGMP (pGC-A) and cAMP (MasR) as read-out (figure 1C-D). As proximal tubular injury is a contributing mechanism of CRS we defined presence of both pGC-A and MasR in human primary proximal tubular (PPT) cells (figure 1E-F). Finally, since renal vasoconstriction in CRS may contribute to renal hypoxia and injury, we defined potential renal vasodilating actions of NPA7 in a canine model of HF (renal blood flow NPA7 vs. baseline: +26.7 ± 13.1 ml/min, p<0.05; urinary flow NPA7 vs. baseline: +0.098 ± 0.024 ml/min, p<0.01).
Conclusion: In conclusion, this study shows that NPA7 is a dual pGC-A/MasR activator in vitro, that its molecular receptor targets are present in human PTT cells, and that NPA7 induces renal vasodilation in an experimental model of HF. Altogether, this study lays the groundwork for further studies on NPA7s cardiorenal protective properties in vivo.
Author Disclosures: L.M. Meems: Research Grant; Significant; ICIN - Netherlands Heart Foundation. B.K. Huntley: None. G.J. Harty: None. S. Pan: None. J.C. Burnett: Research Grant; Significant; NIH RO1 HL36634, Minnesota Regeneration Medicine Program, the Harrington Discovery Institute. Ownership Interest; Modest; Zumbro Discovery, Capricor Therapeutics, Anexon Inc.
- © 2016 by American Heart Association, Inc.