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: 10620864
• 负责人: Seiya Kitamura
• 金额: $ 24.9万
• 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/10620864
• 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; Development; Dimethyl Sulfoxide; Disease; Due Process; Fluorides; Funding; Goals; Health; Heme; In Vitro; Intuition; Laboratory Research; Lead; Leukocyte Elastase; Libraries; Ligands; Liquid substance; Manuals; Measurement; 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; base; biological systems; biomaterial compatibility; cost; cost effective; design; drug candidate; drug development; drug discovery; 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.

项目概要/摘要 高通量筛选方法和仪器的日益普及彻底改变了筛选方法 科学界寻找调节蛋白质功能和细胞途径的小分子。这 针对体外和细胞测定挖掘大量小分子文库的主要目标是识别 化合物用于开发化学工具来操纵生物系统的空间、时间和 浓度依赖性控制，并提供药物开发的关键信息。很遗憾， 大多数初始筛选结果需要广泛的优化才能产生具有必要效力的分子，并且 生物应用的选择性。先导化合物优化是药物和探针开发的一个重大障碍 由于消耗品、人工费用和时间成本高昂，并且依赖直觉和 药物化学家的合成技能。至关重要的是，大多数学术实验室无法获得药物 化学并经常使用低质量的化学探针，这可能会提供误导性的结果。设计一个 因此，通用且具有成本效益的高通量药物化学平台是一个重要的优先事项。 我的应用程序专注于开发、验证和使用实用的综合平台 合成先导化合物类似物库并以高通量方式测试生物活性。我有 最近重新利用亚氨基二氟化硫之间的氟化硫交换（SuFEx）反应 含有（“异二氟”）的分子和胺，在 DMSO 和 PBS 中产生 >80% 的所需产物。我的 令人兴奋的初步研究表明我可以合成皮摩尔先导化合物类似物的集中库 规模，通过体外测定直接评估产品，并开发具有改进的生物学特性的类药物配体 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 我的平台针对一组具有多种体外和基于细胞的蛋白质靶标的全面性 化验（SA2）； 3）将该平台应用于功能片段分子，以识别具有新颖功能的蛋白质靶点 生物学功能。 Wolan、Sharpless、 Cravatt 和 Calibr 将为研究界提供强大的药物化学平台。化学 该平台开发的探针最终将提高我们对基本原理的分子水平理解 生物过程并发现其控制方法。