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.