Novel Peptide Therapeutics for Hypertension

高血压的新型肽疗法

• 批准号: 10077576
• 负责人: John C Burnett
• 金额: $ 61.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077576
• 关键词: Address; African American; Aldosterone; Anti-Inflammatory Agents; Binding; Blood Pressure; Cardiac; Cardiovascular system; Cells; Chemical Structure; Chemosensitization; Chronic; Chronic Kidney Failure; Clinic; Clinical; Clinical Research; Clinical Sciences; Cyclic GMP; Development; Devices; Endothelium; Engineering; Ethnic group; Excretory function; Experimental Models; Foundations; Future; General Population; Generations; Genes; Genetic Variation; Heart failure; Hormones; Human; Hypertension; Impairment; In Vitro; Inbred SHR Rats; Kidney; Lead; Ligands; Metabolic syndrome; Molecular Bank; Natriuresis; Natriuretic Peptides; Neprilysin; Organ; Outcome; Particulate; Pathway interactions; Peptides; Pharmaceutical Preparations; Property; Readiness; Receptor, Angiotensin, Type 1; Reporting; Resistance; Resistant Hypertension; Risk; Sodium; Stroke; Subcutaneous Injections; System; Testing; Time; Translational Research; United States National Institutes of Health; Vasodilation; atrial natriuretic factor receptor A; blood pressure reduction; blood pressure regulation; clinical center; coronary event; design; high risk; high salt diet; high throughput screening; human study; in vivo; innovation; new therapeutic target; next generation; novel; novel therapeutics; peptide drug; positive allosteric modulator; receptor; repository; response; small molecule; small molecule libraries; small molecule therapeutics; synergism

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.

项目概要 本申请的目的是推进具有特殊功能的新型肽疗法治疗高血压 重点关注难治性高血压（RH），美国尚无批准的药物或设备。我们的 策略是针对颗粒鸟苷酸环化酶受体-A/环鸟苷单磷酸（pGC- A/cGMP) 途径，其中心脏激素 ANP 是内源性配体。迄今为止的研究支持 pGC-A/cGMP 通路在血压 (BP) 调节中的关键作用。降血压的机制是 尿钠排泄、血管舒张和醛固酮抑制。除了降血压特性外，该途径还 具有抗肥厚、抗纤维化、抗炎和内皮保护作用。一般来说 人群中，我们和其他人报告了 ANP 基因 (rs5068) 的遗传变异与更高的 ANP、降低血压以及预防高血压 (HTN) 和代谢综合征。我们还报道过早 人类高血压各阶段的特点是 ANP 降低，而重度高血压的特点是 ANP 降低 和较高的醛固酮。重要的是，非裔美国人 (AA) 是一个高风险族群 与其他种族相比，RH 的特点是循环利尿钠肽 (NP) 减少 40% 组。申请人将 MANP 设计为同类最佳的 pGC-A/cGMP 激活剂，具有 增强的 pGC-A/cGMP 激活特性，并且显着抵抗脑啡肽酶的降解。在 实验模型中，MANP在降低血压、增强尿钠和抑制醛固酮方面具有优越性 与ANP相比。在迄今为止唯一的人体研究中，每日一次皮下注射 MANP，连续 3 次 天，在 RH 受试者中，其耐受性良好、安全且大幅降低血压、抑制醛固酮和 增强钠排泄以及 GFR。首先，我们建议定义对 MANP 的响应 具有 RH 的非裔美国人 (AA)。其次，我们将定义慢性心肾保护和RAAS 抑制下一代 MANP（即 MANP2）在自发性高血压大鼠（SHR）中的作用。 第三，我们建议定义两种先导小分子正变构之间的体外协同作用 调节剂 (PAM) 与 MANP2 一起优化 pGC-A 激活。具体目标 1：定义 BP、CV、肾、 使用 Mayo Clinic 临床和治疗中心研究 MANP 在 AA 和 RH 中的神经体液和 cGMP 反应 转化科学 (CCaTS) 临床研究单位 (CRU)。具体目标 2：建立体内慢性 与 Entresto 相比，SHR 中 MANP2 的心肾保护和 RAAS 抑制特性。具体的 目标 3：定义人体中两种主要 PAM 和 MANP2 之间体外 pGC-A/cGMP 激活的协同作用 原代细胞。

项目成果

MANP (M-Atrial Natriuretic Peptide) Reduces Blood Pressure and Furosemide-Induced Increase in Aldosterone in Hypertension.

• DOI: 10.1161/hypertensionaha.121.18837
• 发表时间: 2022-04
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Dzhoyashvili NA;Iyer SR;Chen HH;Burnett JC Jr
• 通讯作者: Burnett JC Jr

Evidence for Angiotensin II as a Naturally Existing Suppressor for the Guanylyl Cyclase A Receptor and Cyclic GMP Generation.

血管紧张素II作为Guanylyl环化酶A受体和环状GMP生成的自然现有抑制剂的证据。

• DOI: 10.3390/ijms24108547
• 发表时间: 2023-05-10
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Ma, Xiao;Iyer, Seethalakshmi R.;Ma, Xiaoyu;Reginauld, Shawn H.;Chen, Yang;Pan, Shuchong;Zheng, Ye;Moroni, Dante G.;Yu, Yue;Zhang, Lianwen;Cannone, Valentina;Chen, Horng H.;Ferrario, Carlos M.;Sangaralingham, S. Jeson;Burnett Jr, John C.
• 通讯作者: Burnett Jr, John C.

Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.

发现小分子鸟苷酸环化酶 A 受体正变构调节剂。

• DOI: 10.1073/pnas.2109386118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Sangaralingham,SJeson;Whig,Kanupriya;Peddibhotla,Satyamaheshwar;Kirby,RJason;Sessions,HamptonE;Maloney,PatrickR;Hershberger,PaulM;Mose-Yates,Heather;Hood,BeckyL;Vasile,Stefan;Pan,Shuchong;Zheng,Ye;Malany,Siobhan;BurnettJr,
• 通讯作者: BurnettJr,

First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension.

• DOI: 10.1161/hypertensionaha.121.17159
• 发表时间: 2021-12
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Chen HH;Wan SH;Iyer SR;Cannone V;Sangaralingham SJ;Nuetel J;Burnett JC Jr
• 通讯作者: Burnett JC Jr

MANP Activation Of The cGMP Inhibits Aldosterone Via PDE2 And CYP11B2 In H295R Cells And In Mice.

• DOI: 10.1161/hypertensionaha.121.18906
• 发表时间: 2022-08
• 期刊: HYPERTENSION
• 影响因子: 8.3
• 作者: Chen, Yang;Iyer, Seethalakshmi R.;Nikolaev, Viacheslav O.;Naro, Fabio;Pellegrini, Manuela;Cardarelli, Silvia;Ma, Xiao;Lee, Hon-Chi;Burnett, John C., Jr.
• 通讯作者: Burnett, John C., Jr.