Despite optimal current
therapies,
cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in
peptide engineering have accelerated the development of innovative
therapeutics for diverse human disease states. Additionally, the advancement of bispecific
therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of
cardiovascular disease. We, therefore, engineered a novel, designer
peptide, which simultaneously targets the pGC-A (particulate
guanylyl cyclase A) receptor and the MasR (Mas receptor), potentially representing an attractive cardiorenoprotective therapeutic for
cardiovascular disease. We engineered a novel, bispecific receptor activator, NPA7, that represents the fusion of a 22-amino
acid sequence of BNP (
B-type natriuretic peptide; an endogenous
ligand of pGC-A) with Ang 1-7 (angiotensin 1-7)-the 7-amino
acid endogenous activator of MasR. We assessed NPA7's dual receptor activating actions in vitro (second messenger production and receptor interaction). Further, we performed an intravenous
peptide infusion comparison study in normal canines to study its
biological actions in vivo, including in the presence of an MasR antagonist. Our in vivo and in vitro studies demonstrate the successful synthesis of NPA7 as a bispecific receptor activator targeting pGC-A and MasR. In normal canines, NPA7 possesses enhanced natriuretic,
diuretic, systemic, and renal vasorelaxing and cardiac unloading properties. Importantly, NPA7's actions are superior to that of the individual native pGC-A or MasR
ligands. These studies advance NPA7 as a novel, bispecific designer
peptide with potential cardiorenal therapeutic benefit for the treatment of
cardiovascular disease, such as
hypertension and
heart failure.