RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins

RP5：自噬蛋白小分子探针的化学蛋白质组学发现

• 批准号: 10364727
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 167.24万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364727
• 关键词: Anti-Infective Agents; Autophagocytosis; Biological; Biological Assay; Biotechnology; Cells; Chemicals; Collaborations; Communicable Diseases; Communities; Complement; Complex; DNA; Data Set; Development; Funding; Genes; Genomics; Goals; Human; Immune response; Immunity; In Situ; Infectious Agent; Infectious Diseases Research; Interferons; Laboratories; Ligands; Maps; Mass Spectrum Analysis; Mediating; Methods; Mining; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Play; Process; Proteins; Proteome; Proteomics; Role; Site; Therapeutic; activity-based protein profiling; analog; base; biological systems; cell type; clinically relevant; innovation; novel; pathogen; programs; protein phosphatase inhibitor-2; screening; small molecule; small molecule libraries; therapeutic development; tool; transcription factor

PROJECT SUMMARY – RP5 Small molecules that enhance autophagy have the potential to serve as therapeutics against a phylogenetically diverse and broad range of pathogens. Nonetheless, most of the proteins that participate in, or regulate, autophagy lack chemical probes and some may even be viewed as undruggable. To accelerate the discovery of chemical probes, and ultimately drugs that promote anti-infective autophagy, new platforms are needed that can broadly and efficiently evaluate small molecule interactions for autophagy-related proteins from diverse structural and functional classes. Our laboratory has recently introduced the first chemical proteomic platforms to globally assess the druggability of proteins directly in native biological systems. These quantitative mass spectrometry-activity-based protein profiling (MS-ABPP) platforms can be applied to any cell type or state and have identified small-molecule hit ligands for many hundreds of proteins across a wide range of classes, including those previously considered undruggable (e.g., adaptors, transcription factors). Mining our current MS-ABPP data sets of the human proteome, which contain 30,000+ sites on 10,000+ proteins, has uncovered evidence of druggability for several proteins involved in degradative autophagy and/or ATG gene- dependent immunity. In RP5, we will use our MS-ABPP platforms in close collaboration with RP1-4 to discover and optimize small-molecule probes that enhance autophagy-mediated defense against infectious diseases. We will pursue the following Specific Aims: 1) the chemical proteomic identification of protein targets of autophagy-stimulating small molecules; 2) the chemical proteomic discovery of hit ligands for prioritized autophagy proteins; 3) the chemical proteomic discovery of novel, druggable proteins that regulate autophagy; and 4) the optimization of chemical probes for prioritized autophagy proteins. RP5 should furnish potent and selective chemical probes for several prioritized autophagy proteins, and these probes will be provided to RP1- 4 for biological studies. The chemical probes developed in RP5 should also serve as much needed tools for the greater autophagy and infectious disease communities, as well as valuable starting points for the development of broad-spectrum anti-infective therapies.

项目摘要 - RP5 增强自噬的小分子有潜力作为对系统发育的治疗 潜水员和广泛的病原体。但是，大多数参与或调节的蛋白质 自噬缺乏化学问题，有些甚至可能被视为不足。加速发现 化学问题，以及最终促进反感染自噬的药物，需要新的平台 可以广泛有效地评估潜水员自噬相关蛋白的小分子相互作用 结构和功能类别。我们的实验室最近引入了第一个化学蛋白质组学 直接在天然生物系统中直接评估蛋白质可药物的平台。这些 基于定量的质谱 - 活性蛋白分析（MS-ABPP）平台可以应用于任何细胞 类型或状态，并确定了数百种蛋白质的小分子命中配体 类别，包括先前认为不可能的那些（例如，适配器，转录因子）。开采我们 当前的人蛋白质组的MS-ABPP数据集，该数据集包含10,000多种蛋白质上的30,000个位点 发现了参与降解自噬和/或ATG基因的几种蛋白质的可药用证据 依赖免疫。在RP5中，我们将与RP1-4密切合作使用MS-ABPP平台来发现 并优化小分子问题，以增强自噬介导的防御性疾病的防御。 我们将追求以下特定目标：1）化学蛋白质组学的鉴定 自噬刺激小分子； 2）优先级的HIT配体的化学蛋白质组学发现 自噬蛋白； 3）调节自噬的新型可药物蛋白的化学蛋白质组学发现； 4）优化优先级自噬蛋白的化学问题。 RP5应该具有潜力和 几种优先自噬蛋白的选择性化学问题，这些问题将提供给RP1- 4用于生物学研究。 RP5中产生的化学问题也应为急需的工具提供 更大的自噬和传染病社区，以及宝贵的起点 开发广谱抗感染疗法。