Novel Peptide Therapeutics for Hypertension

项目摘要 本申请的目的是推进用于高血压的新型肽治疗剂， 重点关注美国尚无获批药物或器械的顽固性高血压（RH）。我们 策略是靶向颗粒鸟苷酸环化酶受体-A/环磷酸鸟苷（pGC-1）， A/cGMP）途径，心脏激素ANP是其内源性配体。迄今为止的研究支持a pGC-A/cGMP途径在血压（BP）调节中的关键作用。降压的机制是 尿钠排泄、血管舒张和醛固酮抑制。除了降低血压的特性，这种途径还 具有抗肥大、抗纤维化、抗炎和内皮保护作用。一般 在人群中，我们和其他人已经报道了ANP基因（rs 5068）的遗传变异与较高的 ANP、降低血压和保护免受高血压（HTN）和代谢综合征。我们还报道说， 人类HTN的阶段以降低的ANP为特征，而重度HTN以较低的ANP为特征 和更高的醛固酮。重要的是，非洲裔美国人（AAs）代表了高风险的种族人群， 与其他种族相比，RH的特征是循环利钠肽（NP）减少40%。 组申请人将MANP设计为同类最佳的pGC-A/cGMP激活剂，其具有 增强的pGC-A/cGMP活化特性，并显著抵抗脑啡肽酶的降解。在 在实验模型中，MANP在降低血压、增强尿钠排泄和抑制醛固酮方面具有上级优势 与ANP相比。在迄今为止唯一的人类研究中，每天一次皮下注射Manp，持续三个月。 天，在RH受试者中耐受性良好，安全且稳健地降低BP，抑制醛固酮， 增加钠排泄以及GFR。首先，我们建议定义响应MANP在 非裔美国人（AAs）RH。其次，我们将定义慢性心肾保护和RAAS 在自发性高血压大鼠（SHR）中抑制下一代MANP（即MANP 2）的作用。 第三，我们建议在体外确定两种铅小分子正变构剂之间的协同作用， 调节剂（PAM）与MANP 2以优化pGC-A活化。具体目标1：定义BP、CV、肾脏， 使用马约诊所的临床和实验室研究中心， 转化科学（CCaTS）临床研究单位（CRU）。具体目标2：在体内建立慢性 与Entresto相比，MANP 2在SHR中的心肾保护和RAAS抑制特性。具体 目的3：在体外确定两种前导PAM和人MANP 2之间在pGC-A/cGMP活化中的协同作用 主要细胞

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.