부산대학교 도서관

Introduction: Bispecific drugs have emerged as highly efficacious medicines as they are designed to target two separate signaling pathways. We engineered a bispecific peptide NPA7 to co-activate the natriuretic peptide (NP) GC-A receptor to which ANP and BNP bind and the Mas receptor (MasR) that is activated by the alternative renin-angiotensin system pathway peptide Angiotensin 1-7. To support our development of NPA7 as a potential therapy in heart failure (HF), we investigated the actions and stability of subcutaneous (SQ) administration of NPA7 in normal canines. Hypothesis: SQ NPA7 is rapidly absorbed, activates cGMP, enhances cardiorenal function and suppresses renin and aldosterone. Second, NPA7 is highly stable in plasma with the GC-A and MasR moieties remaining fused. Methods: Plasma and urinary cGMP, cardiorenal and RAS responses to SQ injection (10μg/kg) were determined over 4 hours in normal canines (n=5) in vivo. Ex vivo, we established stability of NPA7 in canine serum using liquid chromatography-mass spectrometry (LC-MS). Data are expressed as mean±SEM. * P<0.05 vs. BL. Results: In vivo, SQ NPA7 resulted in a sustained increase at 2 hours in plasma (BL:10±3; 120 min:30±6* pmol/ml) and urinary (BL:1033±198; 120 min:5792±857* pmol/min) cGMP, GFR (BL: 29±6; 120 min:70±12* ml/min) and sodium excretion (BL:18±10; 120 min: 144±33* ueq/min). We observed a gradual reduction in BP at 60 min (BL:109±4; 60 min: 99±7* mmHg) with sustained decrease in PCWP at 4 hours (BL:5±0.9; 240 min:3.1±0.6* mmHg). SQ NPA7 also suppressed plasma renin and aldosterone up to 3 hours after SQ injection. LC-MS revealed that NPA7 was highly stable with both the GC-A and MasR activating moieties intact ex vivo in canine serum with a disappearance time of 2 hours. Conclusions: SQ NPA7 has prolonged cGMP activating, cardiorenal enhancing and renin and aldosterone suppressing actions in normal canines. NPA7 is also highly stable in serum. These studies support SQ administration as an effective delivery strategy for NPA7, a first-in-class innovative bispecific dual pGC-A/MasR activator now in preclinical development for HF. [ABSTRACT FROM AUTHOR]