Small Molecule Discovery for GC-A Activators

 描述（由申请人提供）：申请人与其他人一起提出了心脏作为内分泌器官的概念，其中心肌来源的心房利钠肽（ANP）和B型利钠肽（BNP）作为心肾、血压和容量调节激素发挥作用。在释放时，ANP和BNP结合颗粒鸟苷酸受体A（GC-A）并激活cGMP，其第二信使。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活化直接介导具有抗凋亡、抗纤维化、抗肥大、血管内皮再生、脂解和醛固酮抑制特性的器官保护，使得该激素系统成为前所未有的治疗机会，特别是在心血管和代谢疾病的高度临床相关领域。利钠肽GC-A受体在多个器官和细胞类型中具有多效有益特性，其可以保护免于心血管和代谢疾病。到目前为止，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。该申请旨在发现这种新型治疗性小分子。本补助金申请是对PAR-14-284的回应发现化学探针的高通量筛选先前为PAR-12-058-探索化学探针的HTS检测请求），建议马约诊所（罗切斯特，明尼苏达州）和桑福德-伯纳姆医学研究所（Orlando，佛罗里达），通过对来自分子库探针生产中心网络的NIH化合物库进行高通量筛选（HTS）来发现靶向GC-A受体的小分子激动剂。马约诊所的研究人员因其对利钠肽系统的生物学、治疗学和诊断学的广泛研究而获得国际认可，而桑福德-伯纳姆医学研究所在HTS发现小分子方面有着良好的记录。由于HTS测定已到位，因此拟定研究具有高度可行性。此外，由于Sanford-Burnham团队的最先进HTS设备以及基于马约团队的生物学和临床专业知识的药物发现历史，拟议的研究非常新颖。将在马约诊所的人细胞系中进行研究，以验证Sanford-Burnham研究者鉴定和优化的命中。因此，这一提议对目前尚不存在的小分子GC-A激动剂的新药发现具有很高的影响，具有显著降低人类心血管和代谢疾病的巨大负担的潜力。

 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.