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（由适用提供）：申请人与其他人一起将心脏的概念提高为内分泌器官，在该器官中，心房纳二肽（ANP）和B型纳二尿素肽（BNP）的心肌起源起源于心脏，血压，血压和体积调制马匹。释放后，ANP和BNP与特定的Guanylyl受体A（GC-A）结合，并激活其第二个使者CGMP。 GC-A是非常重要的是，尽管受到最佳调节的血管内体积和血压稳态，但GC-A激活直接与抗凋亡，抗纤维化，抗纤维化，抗抗血症性，血管内皮性内皮性再生素，脂肪解析，脂肪解度和高度抑制的体积相关的机器人的抗纤维化，抗肌感染性，抗纤维化，抗血清和抗血管造成的体积，并抑制了无与伦比的体育型，并不是在介导器官的保护。心血管和代谢性疾病。亚钠肽GC-A受体电势在多种器官和细胞类型中的多元有益特性，这些特性可能可以预防心血管和代谢疾病。迄今为止，没有小分子，非肽，可以激活GC-A受体并为这些毁灭性疾病带来改进的治疗。该应用程序旨在发现这种新型的治疗小分子。该赠款的申请是对PAR-14-284（高通量筛查（HTS）发现化学探针的响应；以前是PAR-12-058 pars对HTS的测定法进行HTS进行化学探针），建议对Mayo Clinic（Rochester，Minnesota）和Sanford-Burnham医学研究所（Orlando）（Orlando）（Orlando）（Orlando）（Orlando）（Orlando giver）（Orlando）（Orlando）（Orlando）（Orlando）（Orlando）（Orlando）（Orlando）（Orlando）努力，以实现合作努力来自分子库探测生产中心网络的NIH库的吞吐量筛选（HTS）。梅奥诊所的研究人员因其对纳地钠肽系统的生物学，疗法和诊断的广泛研究而受到国际认可，而桑福德·伯纳姆医学研究所（Sanford-Burnham Medical Research Institute）则在HTS发现了小分子的发现记录。拟议的研究是高度可行的，因为HTS测定已适用。此外，由于Sanford-Burnham团队的最先进的HTS设备以及基于Mayo团队的生物学和临床专业知识，拟议的研究非常新颖。验证Sanford-Burnham研究人员确定和优化的命中的研究将在Mayo Clinic的人类细胞系中进行。该提案对当前不存在的小分子GC-A激动剂的新药物发现具有很高的影响，其潜力显着减少了人类心血管和代谢疾病的巨大燃烧。