Activation of the Secretin Receptor as a Strategy for the Treatment of Heart Failure

激活促胰液素受体作为治疗心力衰竭的策略

• 批准号: 9303747
• 负责人: LAURENCE J MILLER
• 金额: $ 47.5万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303747
• 关键词: AVPR2 gene; Acute; Adverse effects; Age; Agonist; Aliquot; Angiotensin Receptor; Angiotensins; Beta Cell; Biological Assay; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Bradykinin; Cardiac; Cardiac Output; Cardiovascular Diseases; Cell Line; Cells; Chemicals; Chinese Hamster Ovary Cell; Cleaved cell; Clinic; Clinical; Clinical Trials; Contracts; Coupled; Cyclic AMP; Cyclic AMP Receptors; Data; Databases; Dependency; Desire for food; Diabetes Mellitus; Dose; Drug Targeting; EFRAC; Elderly; Endothelin; Epidemic; Event; Exposure to; FDA approved; G-Protein-Coupled Receptors; GLP-I receptor; Generations; Genomics; Glucose; Goals; Heart; Heart failure; Hospitalization; Human; Incidence; Institutes; Institution; Islets of Langerhans; Lead; Libraries; Life Extension; Liquid substance; Mediating; Medical; Medicare; Morbidity - disease rate; Natriuretic Peptides; Neprilysin; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Patient-Focused Outcomes; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Physiological; Population; Property; Protease Inhibitor; PubChem; Public Health; Receptor Cell; Reporting; Robotics; Running; Satiation; Secretin; Signal Transduction; Substance P; Surveys; System; Testing; Therapeutic; United States; Validation; Vascular resistance; Vasopressin Receptor; Vasopressins; analog; base; cheminformatics; coronary perfusion; cytotoxic; cytotoxicity; density; design; drug candidate; drug discovery; enzyme substrate; experience; glucose metabolism; high throughput screening; improved; mortality; novel drug combination; novel therapeutic intervention; peptide hormone; positive allosteric modulator; pre-clinical; programs; receptor; response; scaffold; scale up; screening; secretin receptor; small molecule; stable cell line; standard of care; therapeutic effectiveness; therapeutic target; treatment strategy; valsartan

PROJECT SUMMARY/ABSTRACT Heart failure is a major cause of morbidity and mortality in the population, with the rising incidence of cardiovascular disease contributed to by epidemic increases in the incidence of obesity and associated type 2 diabetes mellitus. Although existing drugs are effective in acutely correcting decompensated heart failure, this continues to be associated with unacceptable rates of rehospitalization and mortality. A new drug combination that adds neprilysin inhibition to the current standard-of-care for heart failure, angiotensin receptor blockade, was approved by the FDA on the basis of extension of the life of patients with reduced cardiac output. However, the very broad action of the peptidase inhibitor in this combination theoretically could be improved, thereby reducing possible side effects and increasing therapeutic effectiveness. The specific enzyme substrate responsible for the beneficial effects of this drug is not yet clear. While it has been assumed to be natriuretic peptides, other peptides are also cleaved, many of which have potential offsetting and/or side effects. Another prominent potentially beneficial substrate of neprilysin is secretin, a peptide hormone with useful effects on cardiac contractility and ejection fraction, coronary perfusion, peripheral vascular resistance, post-cibal satiety, and glucose-sensitive incretin action. There are currently no known drugs that target the secretin receptor, providing these effects. This proposal is designed to develop appropriate assays and to screen for candidates with potential to impact this major public health problem using high throughput screening (HTS). The OBJECTIVE is to identify molecules that enhance signaling at the secretin receptor, either by acting as positive allosteric modulators of secretin action or as direct agonists of this potentially important therapeutic target. This represents a partnership between Dr. Miller, with extensive secretin receptor experience, and Dr. Sergienko, with HTS and chemical genomic expertise. There are three specific aims: (i) Primary and secondary assay implementation and optimization, (ii) HTS using cells expressing human secretin receptor and hit confirmation, and (iii) Hit validation and characterization. The primary assays will focus on intracellular cAMP responses in the CHO-SecR cell line stably expressing wild type human secretin receptor, with the assays run in both positive allosteric modulator mode in the presence of submaximal secretin stimulation and in agonist mode without exposure to secretin. During confirmation, the assays will be repeated with compound concentration- dependency evaluated and using a neuronal cell line that naturally expresses a physiologic density of secretin receptor, NG-108 cells. Parental CHO cells and a CHO cell line expressing the Gs-coupled type 2 vasopressin receptor will be studied as controls to be certain that observed responses are secretin receptor-mediated. Selectivity will be explored using other class B GPCR-expressing cells, and a survey of other signaling events, internalization, cell cytotoxicity, and proliferation will be performed. The goal will be to identify candidates with adequate activity to be tested in pre-clinical systems for proof-of-concept, and ultimately in clinical trials.

项目总结/摘要 心力衰竭是人群发病率和死亡率的主要原因， 肥胖和相关2型糖尿病发病率的流行性增加导致心血管疾病 糖尿病的虽然现有的药物在急性纠正失代偿性心力衰竭方面是有效的，但这 继续与不可接受的再住院率和死亡率相关。一种新的药物组合 它将脑啡肽酶抑制添加到目前治疗心力衰竭的标准治疗中，血管紧张素受体阻滞剂， FDA批准的基础上延长患者的生命减少心输出量。 然而，在该组合中肽酶抑制剂的非常广泛的作用理论上可以得到改善， 从而减少可能的副作用并提高治疗效果。特异性酶底物 这种药物的有益效果的原因尚不清楚。虽然它被认为是利钠的 除了肽之外，其他肽也被切割，其中许多具有潜在的抵消和/或副作用。另一 脑啡肽酶的突出的潜在有益底物是促胰液素，其是一种肽激素， 心肌收缩力和射血分数，冠状动脉灌注，外周血管阻力，进食后饱腹感， 和葡萄糖敏感性肠促胰岛素作用。目前还没有已知的靶向促胰液素受体的药物， 提供这些效果。该提案旨在开发适当的检测方法并筛选候选药物 具有使用高通量筛选（HTS）影响这一主要公共卫生问题的潜力。的 目的是鉴定增强促胰液素受体信号传导的分子， 促胰液素作用的变构调节剂或作为该潜在重要治疗靶点的直接激动剂。这 代表了米勒博士，具有丰富的分泌素受体经验，和谢尔盖博士之间的伙伴关系， 有高温超导和化学基因组学的专业知识有三个具体目标：（一）初级和次级分析 实施和优化，（ii）使用表达人促胰液素受体的细胞的HTS和命中确认， 和（iii）命中验证和表征。主要试验将集中在细胞内cAMP反应， 稳定表达野生型人促胰液素受体的CHO-SecR细胞系， 存在次最大促胰液素刺激时的正变构调节剂模式和激动剂模式 不接触促胰液素。在确认期间，将使用化合物浓度重复测定- 使用天然表达生理密度的促胰液素的神经元细胞系评价依赖性 受体，NG-108细胞。亲本CHO细胞和表达Gs偶联的2型加压素的CHO细胞系 受体作为对照进行研究，以确定观察到的反应是分泌素受体介导的。 选择性将使用其他表达B类GPCR的细胞进行探索，并调查其他信号传导事件， 将进行内化、细胞毒性和增殖。目标将是确定候选人， 在临床前系统中测试足够的活性，以验证概念，并最终在临床试验中进行测试。