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.

项目总结-RP 5 增强自噬的小分子有可能作为治疗药物， 种类繁多的病原体。尽管如此，大多数参与或调节的蛋白质， 自噬缺乏化学探针，有些甚至被认为是不可治疗的。为了加速发现 化学探针，并最终促进抗感染自噬的药物，需要新的平台， 可以广泛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， 结构和功能类。我们的实验室最近推出了第一个化学蛋白质组学 这些平台可以直接在天然生物系统中全面评估蛋白质的可药用性。这些 基于定量质谱活性的蛋白质谱分析（MS-ABPP）平台可应用于任何细胞 类型或状态，并已确定了小分子命中配体的数百种蛋白质在广泛的范围内 类，包括那些以前被认为是不可药的（例如，衔接子、转录因子）。挖掘我们的 目前的MS-ABPP人类蛋白质组数据集包含10，000+蛋白质上的30，000+位点， 发现了参与降解性自噬和/或ATG基因的几种蛋白质的可药用性的证据， 依赖性免疫在RP 5中，我们将使用MS-ABPP平台与RP 1 -4密切合作， 并优化小分子探针，增强自噬介导的防御感染性疾病。 我们将致力于以下具体目标：1）化学蛋白质组学鉴定的蛋白质靶点， 自噬刺激小分子; 2）化学蛋白质组学发现的命中配体优先 自噬蛋白; 3）化学蛋白质组学发现调节自噬的新的可药物化蛋白质; 和4）用于优先化自噬蛋白的化学探针的优化。RP 5应该提供有效的和 选择性化学探针的几个优先的自噬蛋白，这些探针将提供给RP 1- 4生物学研究RP 5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社区，以及有价值的起点， 开发广谱抗感染疗法。