Friday, April 26, 2024
4/26/2024
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.
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