Biodesy Delta System for San Francisco Bay Area Region

旧金山湾区 Biodesy Delta 系统

• 批准号: 9273813
• 负责人: FRANK PATRICK MCCORMICK
• 金额: $ 60万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2018-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273813
• 关键词: Affect; Area; Basic Science; Binding; Biological; Complement; Complex; Data; Disease; Disease Pathway; Dose; Environment; Equipment; Exposure to; Funding; Generations; Grant; Health; Human; Kinetics; Lead; Libraries; Ligand Binding; Ligands; Measurement; Measures; Methods; Minor; Molecular Conformation; Molecular Mechanisms of Action; Molecular Weight; Optics; Pathogenesis; Positioning Attribute; Process; Protein Conformation; Proteins; Research; Research Personnel; Research Project Grants; Resolution; San Francisco; Shapes; Stimulus; Structure; Structure-Activity Relationship; System; Technology; Time; Triage; United States National Institutes of Health; Work; base; design; drug development; drug discovery; experimental study; follow-up; improved; inhibitor/antagonist; novel therapeutics; protein function; protein structure; response; screening; second harmonic; small molecule; therapeutic protein; tool

The relationship between protein structure and function is fundamental for understanding the biological mechanisms that contribute to disease pathogenesis. Proteins are dynamic molecules that are capable of changing their shape, or conformation, in response to changes in their environment and upon ligand binding. Many important therapeutic protein targets undergo conformational change as part of their molecular mechanism of action. Recent drug development strategies have been focused on understanding the effects of small molecules on protein conformation, prompting efforts to rationally design specific and potent conformation-disrupting inhibitors. Thus, tools that can measure conformational changes induced by low- molecular weight modulators are necessary to accelerate the pace of basic research and the drug discovery process. We propose to acquire a Biodesy Delta system to complement the protein structure and characterization equipment that is currently available to investigators in the San Francisco Bay Area Region. The Biodesy Delta platform is based on an optical phenomenon called Second Harmonic Generation (SHG) which can be used to very precisely measure protein conformational changes in real-time following analyte binding or exposure to environmental stimuli. The system can work with any protein target, regardless of size, and a wide variety of ligands, including small molecules, fragments, proteins and mixtures. This high-throughput, automated method can be utilized to analyze thousands of wells per day, as opposed to standard methods that are low-throughput and labor intensive. The SHG conformational signatures provide a high-resolution means of mapping compound structures to function (e.g., activity data) via protein conformation. As a result, the Biodesy platform can be used to enhance primary screening and follow-up work, including protein structure-activity relationship (SAR) studies. Preliminary data that was generated by the major users demonstrates the utility of the SHG method for conducting initial library screening, as well as dose-response measurements, washout experiments, and real-time kinetics for hit triage. The proposed research will be conducted by 4 major PIs who oversee 16 NIH-funded grants. Additionally, 9 minor users will employ the technology in their current research projects. By obtaining the technology proposed in this grant, San Francisco Bay Area regional researchers will be uniquely positioned to accelerate protein characterization and drug discovery efforts. This tool will help revolutionize the understanding of the complex ligand-protein interactions that affect disease pathways which should ultimately lead to discovery of new therapeutics to improve human health.

蛋白质的结构和功能之间的关系是理解生物的基础 导致疾病发生的机制。蛋白质是动态的分子，能够 改变它们的形状或构象，以响应它们环境的变化和配体结合。 许多重要的治疗蛋白质靶点作为其分子的一部分经历构象变化 作用机制。最近的药物开发策略一直专注于了解阿司匹林的效果 蛋白质构象上的小分子，促使人们努力合理地设计特定和有效的 破坏构象的抑制剂。因此，可以测量低-低氧引起的构象变化的工具 为了加快基础研究和药物发现的步伐，分子量调节剂是必不可少的 进程。 我们建议获得一个Biodesy Delta系统来补充蛋白质的结构和特性 旧金山湾区调查人员目前可以使用的设备。Bidesy三角洲 该平台基于一种称为二次谐波产生(SHG)的光学现象，可用于 非常精确地实时测量分析物结合或暴露于 环境刺激。该系统可以与任何蛋白质靶标一起工作，无论其大小如何，以及各种不同的 配体，包括小分子、片段、蛋白质和混合物。这种高吞吐量、自动化的方法 可以用来每天分析数千口井，而不是低吞吐量的标准方法 和劳动密集型。SHG构象特征提供了一种高分辨率的映射手段 通过蛋白质构象发挥作用的化合物结构(例如，活性数据)。因此，Biodesy平台 可用于加强初步筛选和后续工作，包括蛋白质结构-活性关系 (Sar)研究。主要用户生成的初步数据显示了SHG的效用 进行初始文库筛选以及剂量-反应测量、洗脱实验的方法， 以及用于命中分类的实时动力学。 这项拟议的研究将由四个主要的私人投资机构进行，他们负责监督NIH资助的16项拨款。此外，9 较小的用户将在他们目前的研究项目中使用这项技术。通过获得建议的技术 在这笔赠款中，旧金山湾区的区域研究人员将在加速蛋白质方面处于独特的地位 定性和药物发现工作。这一工具将有助于彻底改变对建筑群的理解 配体-蛋白质相互作用影响疾病途径，最终应导致发现新的 改善人类健康的治疗学。