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High throughput infrastructure for reaction screening and bioassays

用于反应筛选和生物测定的高通量基础设施

基本信息

批准号：
10630956
负责人：
Robert Graham Cooks
金额：
$ 94.04万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630956
关键词：
Acceleration Acetylcholinesterase Address Air Bacteria Biological Biological Assay Biological Testing Cancer Biology Chemicals Collaborations Collection Computer software Deposition Development Directed Molecular Evolution Effectiveness Electrospray Ionization Enzyme Kinetics Enzymes Evaluation Extramural Activities In Vitro Infrastructure Ions Joints Laboratories Lead Libraries Malignant neoplasm of prostate Mass Spectrum Analysis Measurement Measures Methods National Center for Advancing Translational Sciences Organic Synthesis Outcome Performance Phase Positioning Attribute Preparation Property Qualitative Methods Reaction Reagent Research Research Personnel Route Sampling Scientist Solvents Spectrometry, Mass, Electrospray Ionization Speed Sulfate Surface System Techniques Technology Testing Training Use Effectiveness Writing analog analytical method bioactive scaffold chemotherapeutic agent cholesterol sulfotransferase cost data acquisition design drug candidate drug discovery experimental study high throughput screening improved insight instrument instrumentation interest ion source ionization technique machine learning method mass spectrometer medical countermeasure milligram nano nanoscale nerve agent new chemical entity new technology next generation novel novel therapeutics reaction rate robotic system scaffold screening therapeutic development

项目摘要

High throughput infrastructure for reaction screening and bioassays Mass spectrometry (MS) is a powerful and widely applicable analytical method for qualitative and quantitative analysis of compounds of all types and sizes. Desorption electrospray ionization (DESI) is an ambient ionization method in which samples are analyzed in the open air by impact of primary droplets. Given the ability to position an array of samples relative to the mass spectrometer, DESI-MS becomes a high throughput (HT) chemical analysis method. The power of MS as an analytical technique is well known but it is less commonly realized that MS can also serve as a preparative method, e.g. it can be used to deposit mass-selected ions on surfaces to create new materials in vacuo. Of significant interest to organic synthesis, a unique feature of DESI is that, upon impact, the spray of solvent used to analyze a reaction mixture generates secondary microdroplets in which reactions may be accelerated en route to the mass spectrometer. It is this remarkable feature that makes DESI- MS a powerful synthetic method combined with a built-in analytical capability. With support of DARPA, we built a high throughput system at Purdue capable of automated reaction screening at a rate greater than 1 reaction mixture per second. We now propose an intramural - extramural collaboration between Purdue and the NCATS ASPIRE laboratory. The UG3 component of the collaboration will focus on designing, fabricating, and testing an improved high throughput system for reaction screening based on DESI-MS. The system will replicate the capabilities of the existing Purdue system and also include new capabilities for small-scale synthesis combined with high throughput bioassays. In the UH3 phase of the proposed study, the system will be transferred to NCATS and used in collaboration with the intramural group. As an initial demonstration of the new high throughput platform capabilities, we will pursue the discovery of novel therapeutics for advanced-stage prostate cancer, for which current chemotherapeutic agents show limited effectiveness. Specifically, this effort will entail large-scale screening and synthesis of potential cholesterol sulfotransferase (SULT2B1b, a currently undrugged biological target) inhibitory compounds, together with late-stage functionalization of bioactive scaffolds to generate a diverse range of analogs. Through this effort, the system will be established as an all-in-one next-generation drug discovery platform, with integrated screening, synthesis, and biological assay capabilities. During the latter stages of the UH3 phase, the versatility of the system will be tested in several other biological applications, including directed evolution and functionalization of acetylcholinesterase reactivators. Successful completion of these tasks will demonstrate the newly constructed high throughput DESI-MS platform to be an efficient method for the discovery and expansion of chemical space towards currently undrugged biological targets.

用于反应筛选和生物测定的高通量基础设施质谱（MS）是一种功能强大且广泛适用的定性和定量分析方法，分析所有类型和大小的化合物。解吸电喷雾电离（DESI）是一种环境电离在露天环境中通过初级液滴的撞击对样品进行分析的方法。鉴于有能力定位相对于质谱仪的样品阵列，EST-MS成为高通量（HT）化学品分析方法MS作为一种分析技术的能力是众所周知的，但很少有人意识到， MS还可以用作制备方法，例如，它可以用于在表面上存款质量选择的离子，以在真空中创造新材料。对有机合成有重大意义的是，DESI的一个独特特征是，在碰撞中，用于分析反应混合物的溶剂喷雾产生次级微滴，其中反应可以在到达质谱仪的途中被加速。正是这一显著特点，使DESI- MS是一种强大的合成方法，结合了内置的分析能力。在DARPA的支持下，普渡大学的高通量系统，能够以大于1个反应的速率进行自动化反应筛选混合物每秒我们现在建议普渡大学和NCATS之间进行校内校外合作 ASPIRE实验室该合作的UG 3组件将专注于设计，制造和测试改进的高通量系统，用于反应筛选的基础上，EST-MS。该系统将复制现有普渡系统的能力，还包括小规模合成的新能力，高通量生物测定。在拟议研究的UH 3阶段，该系统将转移到NCATS 并与校内小组合作使用。作为新的高吞吐量的初步演示，平台的能力，我们将寻求发现新的治疗晚期前列腺癌，目前的化疗剂显示出有限的效力。具体而言，这一努力将需要大规模的筛选和合成潜在的胆固醇磺基转移酶（SULT 2B 1b，一种目前未被开发的生物活性物质，靶向）抑制性化合物，以及生物活性支架的后期功能化，以产生各种各样的类似物。通过这一努力，该系统将被建立为一体化的下一代药物发现平台，具有集成的筛选，合成和生物测定能力。在后一在UH 3阶段的各个阶段，将在其他几个生物应用中测试该系统的多功能性，包括乙酰胆碱酯酶再活化剂的定向进化和功能化。成功完成这些任务将证明新构建的高通量微流控质谱平台是一种有效的方法用于发现和扩展化学空间到目前未加固的生物目标。