From the Cardiorenal Research Laboratory (L.M.G.M., I.A.A., S.P., G.H., Y.C., Y.Z., G.E.H., T.I., D.M.H., S.R.I., S.J.S., J.C.B.), Mayo Clinic, Rochester, MN.
Department of Cardiovascular Medicine (L.M.G.M., I.A.A., S.P., G.H., Y.C., Y.Z., G.E.H., T.I., D.M.H., S.R.I., S.J.S., J.C.B.), Mayo Clinic, Rochester, MN.
Hypertension. 2019 Apr;73(4):900-909. doi: 10.1161/HYPERTENSIONAHA.118.12012.
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.
尽管目前的治疗方法已经很优化，但心血管疾病仍然是全球范围内导致死亡的主要原因。重要的是，肽工程的进步加速了针对多种人类疾病状态的创新疗法的发展。此外，针对 >1 个信号通路的双特异性治疗方法的进步代表了治疗心血管疾病的一种极具创新性的策略。因此，我们设计了一种新型的、设计肽，它同时靶向 pGC-A（颗粒型鸟苷酸环化酶 A）受体和 MasR（Mas 受体），这可能是一种有吸引力的心血管保护治疗药物，用于治疗心血管疾病。我们设计了一种新型的双特异性受体激活剂 NPA7，它代表了 BNP（B 型利钠肽；pGC-A 的内源性配体）的 22 个氨基酸序列与 Ang 1-7（血管紧张素 1-7）的融合 -MasR 的内源性激活剂。我们评估了 NPA7 在体外的双重受体激活作用（第二信使产生和受体相互作用）。此外，我们在正常犬中进行了静脉内肽输注比较研究，以研究其在体内的生物学作用，包括在存在 MasR 拮抗剂的情况下。我们的体内和体外研究表明成功合成了 NPA7，它是一种同时靶向 pGC-A 和 MasR 的双特异性受体激活剂。在正常犬中，NPA7 具有增强的利钠、利尿、全身和肾脏血管舒张以及心脏卸载作用。重要的是，NPA7 的作用优于单个天然 pGC-A 或 MasR 配体。这些研究推进了 NPA7 作为一种新型的双特异性设计肽，具有治疗心血管疾病（如高血压和心力衰竭）的潜在心脏肾脏治疗益处。
