Small Molecule Discovery for GC-A Activators

GC-A 激活剂的小分子发现

基本信息

  • 批准号:
    8962993
  • 负责人:
  • 金额:
    $ 42.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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John C Burnett其他文献

cGMP enhancing strategies for acute and chronic heart failure
  • DOI:
    10.1186/1471-2210-5-s1-s22
  • 发表时间:
    2005-06-16
  • 期刊:
  • 影响因子:
    2.700
  • 作者:
    John C Burnett;Guido Boerrigter
  • 通讯作者:
    Guido Boerrigter
Integrin receptor subtype antagonism augments BNP-mediated cGMP generation in cultured human cardiac fibroblasts: evidence for particulate guanylate cyclase receptor and integrin receptor cross-talk
  • DOI:
    10.1186/1471-2210-7-s1-p30
  • 发表时间:
    2007-07-25
  • 期刊:
  • 影响因子:
    2.700
  • 作者:
    Brenda K Huntley;John C Burnett
  • 通讯作者:
    John C Burnett
Pharmacokinetic and pharmacodynamic study of a novel chimeric natriuretic peptide, CD-NP, in the normal dog
  • DOI:
    10.1186/1471-2210-7-s1-p38
  • 发表时间:
    2007-07-25
  • 期刊:
  • 影响因子:
    2.700
  • 作者:
    Candace YW Lee;Guido Boerrigter;Gail J Harty;John C Burnett
  • 通讯作者:
    John C Burnett
Bioavailability of intravenous versus subcutaneous administration of the dual GC-A and GC-B designer natriuretic peptide cenderitide in healthy canines
  • DOI:
    10.1186/1471-2210-11-s1-p11
  • 发表时间:
    2011-08-01
  • 期刊:
  • 影响因子:
    2.700
  • 作者:
    Guido Boerrigter;Lisa C Costello-Boerrigter;Gail J Harty;John C Burnett
  • 通讯作者:
    John C Burnett

John C Burnett的其他文献

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{{ truncateString('John C Burnett', 18)}}的其他基金

Novel Therapeutics for Cardiovascular Disease
心血管疾病的新疗法
  • 批准号:
    10440006
  • 财政年份:
    2022
  • 资助金额:
    $ 42.21万
  • 项目类别:
Novel Peptide Therapeutics for Hypertension
高血压的新型肽疗法
  • 批准号:
    10077576
  • 财政年份:
    2018
  • 资助金额:
    $ 42.21万
  • 项目类别:
Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure
用于心力衰竭心肾保护的新型肽疗法
  • 批准号:
    9753353
  • 财政年份:
    2017
  • 资助金额:
    $ 42.21万
  • 项目类别:
Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure
用于心力衰竭心肾保护的新型肽疗法
  • 批准号:
    9211673
  • 财政年份:
    2017
  • 资助金额:
    $ 42.21万
  • 项目类别:
Protein Therapeutics to Prevent Heart Failure Post Myocardial Infarction
预防心肌梗塞后心力衰竭的蛋白质疗法
  • 批准号:
    8020951
  • 财政年份:
    2010
  • 资助金额:
    $ 42.21万
  • 项目类别:
Protein Therapeutics to Prevent Heart Failure Post Myocardial Infarction
预防心肌梗塞后心力衰竭的蛋白质疗法
  • 批准号:
    7867072
  • 财政年份:
    2010
  • 资助金额:
    $ 42.21万
  • 项目类别:
Natriuretic Peptide System and Cardiac Fibrosis
利钠肽系统与心脏纤维化
  • 批准号:
    7898654
  • 财政年份:
    2009
  • 资助金额:
    $ 42.21万
  • 项目类别:
Core--Neurohumoral
核心--神经体液
  • 批准号:
    7898658
  • 财政年份:
    2009
  • 资助金额:
    $ 42.21万
  • 项目类别:
Cardiovascular Peptides and Myocardial Infarction
心血管肽与心肌梗塞
  • 批准号:
    7476465
  • 财政年份:
    2006
  • 资助金额:
    $ 42.21万
  • 项目类别:
Cardiovascular Peptides and Myocardial Infarction
心血管肽与心肌梗塞
  • 批准号:
    7269302
  • 财政年份:
    2006
  • 资助金额:
    $ 42.21万
  • 项目类别:

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