Biosensors of GPCR Activation & Inhibition for Drug Discovery

GPCR 激活的生物传感器

基本信息

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
项目类别：
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

项目摘要

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）：配体与 G 蛋白偶联受体 (GPCR) 的亲和力、效力和功效的测量是药理学和药物发现的基础。测量 GPCR 第二信使（例如 cAMP 和磷酸肌醇）产生的细胞功能测定已被常规使用，并且自引入以来概念上保持不变。然而，就其本质而言，第二信使是配体-受体相互作用产生的生物物理事件下游的高度放大和反调节反应。此外，剂量反应曲线忽略了受体配体结合的基本动力学，因此可能为激动剂和拮抗剂效力测量提供误导性结果。随着坎地沙坦、马拉维罗等成功治疗药物的表征，动力学特性决定 GPCR 靶向药物临床效用的改善的潜力正变得越来越广泛。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功效很少见。我们假设，在大多数化合物的药物化学检测级联早期，而不是对一些高级化合物回顾性地利用这些特性，将提高药物化学工作的整体效率。最近，GPCR 生物传感器已被开发出来，通过荧光共振能量转移的变化来测量结合动力学和内在功效，作为受体构象的函数，独立于其他细胞成分。我们建议将这些生物传感器调整为药物发现环境中的常规使用，并测试这种方法对其他几种具有潜在治疗意义的 GPCR 的可转移性。该项目将定义一条路径，通过该路径可以开发和验证用于药物发现应用的生物传感器，并且将开发特定传感器以实现多种药物发现计划。由于这是最大的经过验证的药物靶标家族，因此增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。公共健康相关性：该项目的目标是开发用于药物发现的 GPCR 生物传感器，以便提供一种常规测量配体结合动力学和内在功效的方法。如果成功，这将提高药物化学家设计作用于 GPCR 靶点的药物的能力，这些药物可能对多种人类疾病有用。