Novel Peptide Therapeutics for Hypertension

项目总结 本申请的目的是通过一种特殊的多肽治疗高血压的新药物 重点关注在美国没有批准的药物或设备治疗的顽固性高血压(RH)。我们的 策略是靶向颗粒鸟苷环化酶受体-A/环鸟苷一磷酸(PGC-1)。 A/cGMP)途径，心脏激素ANP是其内源性配体。到目前为止的研究支持 PGC-A/cGMP通路在血压调节中的关键作用。降血压的作用机制是 利钠、血管扩张和醛固酮抑制。除了降低血压的特性外，这一途径还 具有抗肥大、抗纤维化、抗炎和内皮保护作用。大体上 我们和其他人已经报道了ANP基因的一个遗传变异(Rs5068)与更高的 心钠素，降低血压，预防高血压和代谢综合征。我们也早些时候报道过， 人类HTN分期以心钠素降低为特征，重度HTN以心钠素降低为特征 和更高的醛固酮。重要的是，非裔美国人(AA)代表了患癌症的高危人群 与其他种族相比，Rh和Rh的特点是循环利钠肽(NPs)减少了40% 组。申请者将MANP设计为同类中最好的PGC-A/cGMP激活剂，它具有 增强了PGC-A/cGMP的活化性能，并显著抵抗奈普利辛的降解。在……里面 实验模型显示，MANP具有明显的降压、利钠、抑制醛固酮作用 与ANP相比。在迄今为止的唯一一项人类研究中，每天一次皮下注射MANP，共三次 天，RH受试者耐受性良好，安全而有力地降低了血压，抑制了醛固酮和 增加钠排泄和肾小球滤过率。首先，我们建议定义对MANP的响应性 患有RH的非裔美国人(AA)。第二，我们将定义慢性心肾保护和RAAS 下一代MANP(即MANP2)对自发性高血压大鼠(SHR)的抑制作用。 第三，我们建议定义两个铅小分子正变构之间的体外协同作用。 带有MANP2的调制器(PAM)可优化PGC-A激活。具体目标1：定义BP、CV、肾脏、 应用梅奥临床和临床研究中心对AAS合并RH患者MANP的神经体液和cGMP反应 翻译科学(CCATS)临床研究单位(CRU)。具体目标2：在体内建立慢性 与Entresto相比，SHR中MANP2的心肾保护和RAAS抑制特性。特定的 目的3：确定PGC-A/cGMP体外激活中两种铅PAM与MANP2之间的协同作用 原生细胞。

PROJECT SUMMARY The objective of this application is to advance novel peptide therapeutics for hypertension with a special focus on resistant hypertension (RH) for which there are no approved drugs or devices in the US. Our strategy is to target the particulate guanylyl cyclase receptor-A/cyclic guanosine monophosphate (pGC- A/cGMP) pathway for which the cardiac hormone ANP is an endogenous ligand. Studies to date support a key role for the pGC-A/cGMP pathway in blood pressure (BP) regulation. The mechanism of BP lowering is natriuresis, vasodilation and aldosterone suppression. Beyond BP lowering properties, this pathway also possesses anti-hypertrophic, anti-fibrotic, anti-inflammatory and endothelial protective actions. In the general population, we and others have reported a genetic variation of the ANP gene (rs5068) is associated with higher ANP, lower BP and protection from hypertension (HTN) and metabolic syndrome. We also reported that early stages of human HTN are characterized by reduced ANP, while severe HTN is characterized by lower ANP and higher aldosterone. Importantly, African Americans (AAs) represent an ethnic population at high risk for RH and are characterized by a 40% reduction in circulating natriuretic peptides (NPs) compared to other ethnic groups. The applicants designed MANP as a best-in-class pGC-A/cGMP activator, which possesses enhanced pGC-A/cGMP activating properties, and is markedly resistant to degradation by neprilysin. In experimental models, MANP is superior in lowering BP, enhancing natriuresis and suppressing aldosterone compared to ANP. In the only human study to date, once daily subcutaneous injection of MANP, for three days, in subjects with RH was well tolerated, safe and robustly reduced BP, suppressed aldosterone and enhanced sodium excretion as well as GFR. First, we propose to define the responsiveness to MANP in African Americans (AAs) with RH. Second, we will define the chronic cardiorenal protective and RAAS suppressing actions of a next generation MANP (i.e. MANP2) in spontaneously hypertensive rats (SHRs). Third, we propose to define synergism in vitro between two lead small molecule positive allosteric modulators (PAMs) with MANP2 to optimize pGC-A activation. Specific Aim 1: Define BP, CV, renal, neurohumoral, and cGMP responses of MANP in AAs with RH using Mayo Clinic's Center for Clinical and Translational Science (CCaTS) Clinical Research Unit (CRU). Specific Aim 2: Establish in vivo the chronic cardiorenal protective and RAAS suppressing properties of MANP2 in SHRs compared to Entresto. Specific Aim 3: Define synergy in pGC-A/cGMP activation, in vitro, between two lead PAMs and MANP2 in human primary cells.