Small Molecule Discovery for GC-A Activators

GC-A 激活剂的小分子发现

• 批准号: 8962993
• 负责人: John C Burnett
• 金额: $ 42.21万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962993
• 关键词: Adipocytes; Adrenal Glands; Agonist; Aldosterone; Apoptotic; Applications Grants; Area; Atrial Natriuretic Factor; Binding; Biological; Biological Assay; Biology; Blood Pressure; Blood Vessels; Brain natriuretic peptide; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cataloging; Catalogs; Cells; Chemicals; Chronic; Clinic; Clinical; Clinical Trials; Congestive Heart Failure; Cyclic GMP; Development; Diagnostic; Disease; Dose; Endocrine Glands; Endocrine system; Equipment; Exhibits; Exposure to; Fibroblasts; Florida; Foundations; Genes; Genetic Variation; Genomics; Glomerular Mesangial Cell; Goals; Guanylate Cyclase; Heart; Heart Hypertrophy; Heart failure; Hormones; Human; Human Cell Line; Hypertension; In Vitro; Injection of therapeutic agent; Insulin; Kidney; Lead; Libraries; Mediating; Medical Research; Metabolic; Metabolic Diseases; Metabolic syndrome; Minnesota; Molecular; Molecular Bank; Myocardial; Natriuretic Peptides; Natural regeneration; Organ; Particulate; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Population; Population Study; Production; Property; Pump; Receptor Signaling; Recording of previous events; Relative (related person); Reporting; Research; Research Institute; Research Personnel; Second Messenger Systems; Signal Pathway; Smooth Muscle Myocytes; Structure-Activity Relationship; System; Therapeutic; Time; United States National Institutes of Health; Vascular Endothelial Cell; analog; atrial natriuretic factor receptor A; base; blood pressure regulation; cell type; clinical practice; clinically relevant; drug discovery; genetic variant; high risk; high throughput screening; human disease; hypertensive heart disease; improved; innovation; novel; novel therapeutics; peptide B; pre-clinical; public health relevance; receptor; repository; response; screening; second messenger; small molecule

 DESCRIPTION (provided by applicant): The applicants, with others, have advanced the concept of the heart as an endocrine organ in which atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) of myocardial origin functions as a cardiorenal, blood pressure, and volume-regulating hormone. Upon release, ANP and BNP bind to particulate guanylyl receptor A (GC-A) and activate cGMP, its second messenger. GC-A is highly expressed in the heart, kidney, adrenals, vasculature, and adipocytes. Importantly, while optimally regulating intravascular volume and blood pressure homeostasis, GC-A activation directly mediates organ protection with anti-apoptotic, anti-fibrotic, anti- hypertrophic, vascular endothelial regeneratin, lipolytic, and aldosterone suppressing properties rendering this hormonal system an unprecedented therapeutic opportunity especially in the highly clinically relevant area of cardiovascular and metabolic disease. The natriuretic peptide GC-A receptor possesses pleotropic beneficial properties in multiple organs and cell types, which may protect against cardiovascular and metabolic disease. To date, there are no small molecule, non-peptide, drugs in existence to activate the GC-A receptor and bring improved therapeutics to these devastating diseases. This application seeks to provide discovery of such a novel therapeutic small molecule. This grant application is in response to PAR-14-284 (High Throughput Screening (HTS) to Discover Chemical Probes; previously PAR-12-058-Solicitation of Assays for HTS to Discovery Chemical Probes), proposes a collaborative effort between Mayo Clinic (Rochester, Minnesota) and Sanford-Burnham Medical Research Institute (Orlando, Florida) to discover small molecular agonists targeting the GC-A receptor by high throughput screening (HTS) of the NIH library of compounds from the Molecular Libraries Probe Production Center Network. The Mayo Clinic investigators are internationally recognized for their extensive research on the biology, therapeutics and diagnostics of the natriuretic peptide system, while the Sanford-Burnham Medical Research Institute has a proven record of discovery of small molecules by HTS. The proposed studies are highly feasible because the HTS assays are in place. Further, the proposed studies are highly novel due to the state-of-the-art HTS equipment of the Sanford-Burnham team and the history of drug discovery built on the biological and clinical expertise of the Mayo team. Studies to validate the hits identified and optimized by the Sanford-Burnham investigators will be done in human cell lines at Mayo Clinic. Thus this proposal has the high impact of novel drug discovery for a small molecule GC-A agonist, which currently does not exist, with the potential of markedly reducing the immense burden of human cardiovascular and metabolic disease.

 描述（由申请人提供）：申请人与其他人提出了心脏作为内分泌器官的概念，其中心房钠尿肽（ANP）和心肌来源的B型钠尿肽（BNP）起到心肾、血压和容量调节激素的作用。释放后，ANP 和 BNP 与颗粒鸟苷酸受体 A (GC-A) 结合并激活其第二信使 cGMP。 GC-A 在心脏、肾脏、肾上腺、脉管系统和脂肪细胞中高度表达。重要的是，在最佳调节血管内容量和血压稳态的同时，GC-A 激活直接介导器官保护，具有抗凋亡、抗纤维化、抗肥厚、血管内皮再生、脂解和醛固酮抑制特性，使该激素系统成为前所未有的治疗机会，特别是在临床高度相关的领域 心血管和代谢疾病。利钠肽 GC-A 受体在多种器官和细胞类型中具有多效性有益特性，可以预防心血管和代谢疾病。迄今为止，还没有小分子、非肽类药物可以激活 GC-A 受体并为这些毁灭性疾病带来改进的治疗方法。本申请旨在发现这种新型治疗性小分子。该拨款申请是为了响应 PAR-14-284（发现化学探针的高通量筛选 (HTS)；之前的 PAR-12-058-发现化学探针的 HTS 测定征集），提议 Mayo Clinic（明尼苏达州罗切斯特）和 Sanford-Burnham 医学研究所（佛罗里达州奥兰多）之间合作，通过高通量发现针对 GC-A 受体的小分子激动剂 对来自分子库探针生产中心网络的 NIH 化合物库进行筛选 (HTS)。梅奥诊所的研究人员因其在利尿钠肽系统的生物学、治疗学和诊断方面的广泛研究而获得国际认可，而桑福德-伯纳姆医学研究所则拥有 HTS 发现小分子的可靠记录。由于 HTS 测定已经到位，因此拟议的研究非常可行。此外，由于 Sanford-Burnham 团队拥有最先进的 HTS 设备以及建立在 Mayo 团队的生物学和临床专业知识基础上的药物发现历史，拟议的研究非常新颖。验证桑福德-伯纳姆研究人员识别和优化的命中的研究将在梅奥诊所的人类细胞系中进行。因此，该提案对目前尚不存在的小分子GC-A激动剂的新药发现具有重大影响，有可能显着减轻人类心血管和代谢疾病的巨大负担。