Biosensors of GPCR Activation & Inhibition for Drug Discovery

GPCR 激活的生物传感器

• 批准号: 7801639
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 23.79万
• 依托单位: CRINETICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2010-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801639
• 关键词: Adrenergic Agents; Affinity; Agonist; Binding; Biological Assay; Biophysics; Biosensor; Cells; Characteristics; Clinical; Code; Coupling; Cyclic AMP; Dissociation; Dose; Drug Delivery Systems; Drug Design; Environment; Event; Family; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; Goals; Inositol Phosphates; KISS1R gene; Kinetics; Label; Ligand Binding; Ligands; Measurement; Measures; Methods; Molecular Conformation; Nature; Noise; Parathyroid Hormones; Peptides; Pharmaceutical Chemistry; Pharmacology; Phase; Preparation; Production; Property; Proteins; Protocols documentation; Public Health; Purinergic P1 Receptors; Receptor Activation; Second Messenger Systems; Signal Transduction; System; Techniques; Testing; Therapeutic; Time; Translating; adrenergic; base; drug discovery; fluorophore; human PTH protein; human disease; improved; in vivo; interest; neglect; programs; public health relevance; radioligand; receptor; receptor expression; receptor function; response; second messenger; sensor; tool

DESCRIPTION (provided by applicant): Measurements of the affinity, potency and efficacy of ligands to G protein-coupled receptors (GPCRs) are fundamental to pharmacology and drug discovery. Cellular functional assays measuring the production of GPCR second messengers such as cAMP and inositol phosphates, are used routinely and remain conceptually unchanged since their introduction. However, by their nature 2nd messengers are highly amplified and counter-regulated responses well downstream of the biophysical events resulting from ligand-receptor interactions. Further, dose response curves neglect the underlying kinetics of receptor ligand binding and can therefore give misleading results for both agonist and antagonist potency measurements. The potential for kinetic properties to determine improved clinical utility of GPCR targeted drugs is becoming more broadly appreciated with the characterization of successful therapeutics such as candesartan, maraviroc and others. However, the measurement binding kinetics and intrinsic efficacy in a drug discovery setting is rare due to the lack of appropriate methods. We hypothesize that availability of these properties early in the medicinal chemistry assay cascade for most compounds, rather than retrospectively for a few advanced compounds, will improve the overall efficiency of medicinal chemistry efforts. Recently, GPCR biosensors have been developed to measure binding kinetics and intrinsic efficacy by changes in Fluorescence Resonance Energy Transfer as a function of receptor conformation, independent of other cellular components. We propose to adapt these biosensors for routine use in a drug discovery environment and test the transferability this approache to several additional GPCR's of potential therapeutic interest. This project will define a path by which biosensors can be developed and validated for drug discovery applications and specific sensors will be developed to enable multiple drug discovery programs. Since this is the largest family of validated drug targets, general tools which enhance medicinal chemistry efforts to create efficacious therapeutics are likely to have a significant long term impact on public health. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop GPCR biosensors for use in drug discovery in order to provide a method for routine measurement of ligand binding kinetics and intrinsic efficacy. If successful, this will improve the ability of medicinal chemists to design drugs which act at GPCR targets that may be useful for a wide range of human diseases.

描述(由申请人提供)：测量配体对G蛋白偶联受体(GPCRs)的亲和力、效力和效力是药理学和药物发现的基础。细胞功能分析测量cAMP和肌醇磷酸盐等gpr第二信使的产生是常规使用的，自问世以来在概念上保持不变。然而，从本质上讲，第二信使是高度放大和反向调节的反应，远远落后于配体-受体相互作用产生的生物物理事件。此外，剂量反应曲线忽略了受体配体结合的潜在动力学，因此对于激动剂和拮抗剂效力的测量可能会给出误导性的结果。随着坎地沙坦、马拉韦罗等成功疗法的出现，动力学特性决定GPCR靶向药物临床有效性改善的潜力正得到越来越广泛的认识。然而，由于缺乏适当的方法，在药物发现环境中测量结合动力学和内在有效性的情况很少见。我们假设，在大多数化合物的药物化学分析级联的早期获得这些特性，而不是追溯到少数高级化合物，将提高药物化学工作的整体效率。最近，GPCR生物传感器已经被开发出来，通过荧光共振能量转移作为受体构象的函数来测量结合动力学和内在有效性，而不依赖于其他细胞成分。我们建议将这些生物传感器用于药物发现环境中的常规使用，并测试这种方法对其他几种潜在治疗兴趣的GPCR的可转移性。该项目将确定一条开发和验证用于药物发现应用的生物传感器的途径，并将开发特定的传感器以实现多种药物发现计划。由于这是经过验证的药物靶标的最大家族，加强药物化学努力以创造有效疗法的通用工具可能会对公众健康产生重大的长期影响。 公共卫生相关性：该项目的目标是开发用于药物发现的GPCR生物传感器，以提供一种常规测量配体结合动力学和内在有效性的方法。如果成功，这将提高药物化学家设计药物的能力，这些药物作用于GPCR目标，可能对广泛的人类疾病有用。