Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide NPA7
Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide NPA7
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DOI：
10.1161/hypertensionaha.118.12012
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发表时间：
2019-04-01
期刊：
影响因子：
8.3
通讯作者：
Burnett, John C., Jr.
中科院分区：
文献类型：
--
作者：
Meems, Laura M. G.;Andersen, Ingrid A.;Burnett, John C., Jr.
尽管目前有最佳的治疗方法，但心血管疾病仍然是全球死亡的主要原因。重要的是，肽工程的进步加速了针对不同人类疾病状态的创新疗法的发展。此外，靶向>1个信号传导通路的双特异性治疗剂的进展代表了治疗心血管疾病的高度创新策略。因此，我们设计了一种新的设计肽，它同时靶向pGC-A（颗粒鸟苷酸环化酶A）受体和MasR（Mas受体），可能代表了一种有吸引力的心血管疾病的心血管保护治疗。我们设计了一种新的双特异性受体激活剂NPA 7，其代表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）-MasR的7个氨基酸内源性激活剂的融合。我们评估了NPA 7的体外双重受体激活作用（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，以研究其体内生物学作用，包括在MasR拮抗剂存在下。我们的体内和体外研究证明了NPA 7作为靶向pGC-A和MasR的双特异性受体激活剂的成功合成。在正常犬中，NPA 7具有增强的利钠、利尿、全身和肾脏血管舒张和心脏卸载特性。重要的是，NPA 7的作用上级于单个天然pGC-A或MasR配体。这些研究推进了NPA 7作为一种新型的双特异性设计肽，其具有治疗心血管疾病如高血压和心力衰竭的潜在心肾治疗益处。
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.