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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