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.

项目摘要 该应用的目的是通过特殊 专注于美国没有批准的药物或设备的耐药性高血压（RH）。我们的 策略是靶向颗粒鸟叶基环酶受体-A/环状鸟苷单磷酸盐（PGC-）（PGC-） A/CGMP）途径为心激素ANP是内源性配体。迄今为止的研究支持 PGC-A/CGMP途径在血压（BP）调节中的关键作用。 BP降低的机制是 纳特里雷SIS，血管舒张和醛固酮抑制。除了BP降低特性之外，此途径也 具有抗肌营养性，抗纤维化，抗炎和内皮保护作用。一般 人口，我们和其他人报告了ANP基因的遗传变异（RS5068）与较高的 ANP，下BP和防止高血压（HTN）和代谢综合征的保护。我们还报告了早期 人类HTN的阶段的特征是ANP降低，而严重的HTN的特征是ANP较低 和更高的醛固酮。重要的是，非洲裔美国人（AAS）代表着具有高风险的种族 RH，其特征是与其他种族相比，循环前尿肽（NP）降低了40％ 组。申请人将MANP设计为一流的PGC-A/CGMP激活剂，它具有 增强了PGC-A/CGMP激活特性，并明显抵抗Neprilysin的降解。在 实验模型，MANP在降低BP，增强Natriuresis和抑制醛固酮方面表现出色 与ANP相比。在迄今为止唯一的人类研究中，每天一次地下注射MANP，三个 天数，在患有RH的受试者中，宽容，安全且可靠地降低了BP，抑制醛固酮和 增强的钠排泄和GFR。首先，我们建议定义对MANP的响应 与RH的非裔美国人（AAS）。其次，我们将定义慢性心脏保护和RAAS 抑制自发性高血压大鼠（SHR）中下一代MANP（即MANP2）的作用。 第三，我们建议在两个铅小分子阳性变构之间定义体外的协同作用 带有MANP2的调节器（PAMS）以优化PGC-A激活。特定目标1：定义BP，CV，肾脏， 使用Mayo Clinic的临床和RH，AAS中MANP的Neurohumoral和CGMP响应 翻译科学（CCAT）临床研究部（CRU）。特定目标2：在体内建立慢性 与Entresto相比，SHR中MANP2的心脏保护性和RAA抑制了MANP2的特性。具体的 AIM 3：在PGC-A/CGMP激活中定义协同作用，在体外，在两个铅PAM和MANP2之间的人类中定义协同作用 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.

• 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,

C-type natriuretic peptide: the heart's guardian angel.

• DOI: 10.1093/eurheartj/ehz142
• 发表时间: 2020-03-01
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Sangaralingham SJ;Chen Y;Burnett JC
• 通讯作者: Burnett JC

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.