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可能作为系统发育上的治疗药物 病原体种类繁多且范围广泛。尽管如此，大多数参与或调节的蛋白质 自噬缺乏化学探针，有些甚至可能被认为是不可成药的。为了加速发现 化学探针，以及最终促进抗感染自噬的药物，需要新的平台 可以广泛而有效地评估来自不同来源的自噬相关蛋白的小分子相互作用 结构类和功能类。我们实验室最近推出了第一个化学蛋白质组学 直接在天然生物系统中全面评估蛋白质成药性的平台。这些 基于活性的定量质谱分析 (MS-ABPP) 平台可应用于任何细胞 类型或状态，并已鉴定出广泛范围内数百种蛋白质的小分子命中配体 类别，包括以前被认为不可成药的类别（例如，接头、转录因子）。挖掘我们的 目前人类蛋白质组的 MS-ABPP 数据集包含 10,000 多个蛋白质的 30,000 多个位点， 发现了几种参与降解自噬和/或 ATG 基因的蛋白质的成药性证据 依赖性免疫。在 RP5 中，我们将使用我们的 MS-ABPP 平台与 RP1-4 密切合作来发现 并优化小分子探针，增强自噬介导的传染病防御能力。 我们将追求以下具体目标：1）蛋白质靶标的化学蛋白质组学鉴定 刺激自噬的小分子； 2) 优先选择命中配体的化学蛋白质组学发现 自噬蛋白； 3) 调节自噬的新型药物蛋白的化学蛋白质组学发现； 4）优化优先自噬蛋白的化学探针。 RP5 应提供有效且 针对几种优先自噬蛋白的选择性化学探针，这些探针将提供给 RP1- 4 用于生物学研究。 RP5 中开发的化学探针也应该作为急需的工具 更大的自噬和传染病群落，以及有价值的起点 开发广谱抗感染疗法。