A universal high-throughput platform to improve biological functions of small molecules

改善小分子生物学功能的通用高通量平台

• 批准号: 10668534
• 负责人: Seiya Kitamura
• 金额: $ 24.83万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668534
• 关键词: Academia; Acoustics; Amines; Biochemical; Biological; Biological Assay; Biological Models; Biological Process; Biological Testing; Biology; Cell Survival; Cells; Cellular Assay; Chemicals; Chemistry; Collaborations; Collection; Communities; Consumption; Derivation procedure; Development; Dimethyl Sulfoxide; Disease; Fluorides; Funding; Goals; Health; Heme; In Vitro; Intuition; Laboratory Finding; Laboratory Research; Lead; Leukocyte Elastase; Libraries; Ligands; Liquid substance; Manuals; Measurement; Medicine; Methods; Mining; Modeling; Molecular; Molecular Chaperones; Pathway interactions; Peptide Hydrolases; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Process; Proteins; Reaction; Regulatory T-Lymphocyte; Research; Research Personnel; Serine Hydrolase; Solubility; Sulfur; T cell differentiation; Testing; Time; United States National Institutes of Health; Validation; analog; biological systems; biomaterial compatibility; cost; cost effective; design; drug candidate; drug development; drug discovery; drug-like compound; high throughput screening; high throughput technology; improved; in vitro Assay; inhibitor; instrument; lead optimization; miniaturize; novel; process optimization; programs; protein function; screening; skills; small molecule; small molecule libraries; tool; transcription factor

PROJECT SUMMARY/ABSTRACT The increased accessibility of high-throughput screening methods and instruments has revolutionized how the scientific community searches for small molecules that modulate protein function and cellular pathways. The primary goal of mining large collections of small-molecule libraries against in vitro and cellular assays is to identify compounds for the development of chemical tools to manipulate biological systems with spatial, temporal, and concentration-dependent control, as well as provide critical information on drug development. Unfortunately, most initial screening hits require extensive optimization to yield molecules with the necessary potency and selectivity for biological applications. Lead optimization is a significant hurdle in the drug and probe development process due to the costly amounts of consumables, labor expenses and time, and reliance on the intuition and synthetic skills of medicinal chemists. Critically, a majority of academic labs do not have access to medicinal chemistry and often use low-quality chemical probes that may provide misleading results. The design of a universal and cost-effective high-throughput medicinal chemistry platform is therefore a significant priority. My application is focused on the development, validation, and use of a practical, comprehensive platform to synthesize lead compound analog library and test biological activity in an high-throughput manner. I have recently repurposed sulfur(VI) fluoride exchange (SuFEx) reactions between iminosulfur oxydifluoride (“isodifluor”)-containing molecules and amines that yield >80% of the desired product in DMSO and PBS. My exciting initial studies show that I can synthesize a focused libraries of lead compound analogs on picomole scale, directly assess the products with in vitro assays, and develop drug-like ligands with improved biological functions. Here, my goals are to: 1) develop, streamline and validate the platform (SA1); 2) rigorously assess the comprehensiveness of my platform against a panel of protein targets with diverse in vitro and cell-based assays (SA2); and 3) apply the platform to functional fragment molecules to identify protein targets with novel biological functions. The successful completion of this highly collaborative study among the Wolan, Sharpless, Cravatt, and Calibr will provide a robust medicinal chemistry platform for the research community. Chemical probes developed by the platform will ultimately improve our molecular-level understanding of fundamental biological processes and discovering approaches to their control.

项目摘要/摘要 高通量筛选方法和工具的可访问性提高，彻底改变了 科学界正在寻找调节蛋白质功能和细胞途径的小分子。 针对体外和细胞测定法挖掘大量小分子库的主要目标是确定 用于开发化学工具以通过空间，临时和 浓度依赖性控制，并提供有关药物开发的关键信息。很遗憾， 大多数初始筛选命中都需要广泛的优化，以产生必要的效力和 生物应用的选择性。铅优化是药物和探针开发的重大障碍 流程由于昂贵的消耗品，劳动力和时间以及对直觉的救济以及 医学化学家的合成技能。至关重要的是，大多数学术实验室无法获得医学化学家。 化学，通常使用低质量的化学问题，这可能会带来误导性结果。设计的设计 因此，普遍且具有成本效益的高通量药物化学平台是重中之重。 我的应用集中于开发，验证和使用实用，全面的平台 以高通量方式合成铅化合物模拟库和测试生物学活性。我有 最近重新利用的硫（VI）氟化物交换（Sufex）反应 （“异地氟”） - 包含在DMSO和PBS中产生的分子和胺的分子和胺。我的 令人兴奋的初始研究表明，我可以合成Picomole上的铅化合物类似物的重点库 比例尺，通过体外评估直接评估产品，并发展具有改善生物学的药物样配体 功能。在这里，我的目标是：1）开发，简化和验证平台（SA1）； 2）严格评估 我的平台对具有潜水员的体外和基于细胞的蛋白质靶标的全面性 测定（SA2）; 3）将平台应用于功能片段分子以鉴定具有新颖的蛋白质靶标 生物功能。这项高度协作的研究成功完成了Wolan，Sharpless， Cravatt和Calibr将为研究社区提供强大的医学化学平台。化学 平台开发的问题最终将改善我们对基本的分子层面的理解 生物过程和发现其控制的方法。