A comprehensive solution for native top down mass spectrometry data analyses across structural biology and biopharma

跨结构生物学和生物制药的原生自上而下质谱数据分析的综合解决方案

• 批准号: 10384677
• 负责人: Kenneth Durbin
• 金额: $ 76.42万
• 依托单位: PROTEINACEOUS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384677
• 关键词: 3-Dimensional; Address; Adopted; Algorithms; Amino Acid Sequence; Antibodies; Binding; Bioinformatics; Biological Process; Clinical; Complex; Computer software; Cryoelectron Microscopy; Data; Data Analyses; Databases; Development; Disease; Electron Microscopy; Elements; Ensure; Family; Grant; Heterogeneity; Individual; Industry; Informatics; Intuition; Ions; Learning; Ligand Binding; Ligands; Maps; Mass Spectrum Analysis; Modification; Molecular Weight; Names; Pathway Analysis; Peptides; Pharmaceutical Preparations; Phase; Protein Complex Subunit; Protein Databases; Proteins; Research; Scientist; Side; Software Tools; Structural Biologist; Techniques; Therapeutic Studies; Time; Validation; Visualization; Work; X-Ray Crystallography; algorithm development; complex data; drug development; experience; experimental study; high throughput analysis; improved; industry partner; insight; mass spectrometer; novel; pre-clinical; protein complex; protein structure; screening; search engine; small molecule; stoichiometry; structural biology; success; therapeutic development; therapeutic protein; tool

PROJECT SUMMARY Native top down mass spectrometry is continuing to evolve into a powerhouse analytical technique that can generate transformative data on the native state of proteoforms and protein complexes. Technological advances in mass spectrometers have spurred the rapid rise of nTDMS over recent years, paving impressive avenues for structural biology research and protein therapeutics development. For instance, new insights into non-covalent ligand binding and localization can be revealed by nTDMS data that are complementary to traditional structural biology approaches such as electron microscopy and NMR. Drug developers can apply nTDMS to study therapeutic proteins in preclinical and clinical settings to learn more about modifications that are present and the complexes being formed. The number of novel protein and protein complex drug molecules is ever increasing, each with a host of difficult analytical and data analysis challenges. On the bioinformatics side of nTDMS, strides have been made in algorithmic development for mass determination of large molecules; however, no fully featured analysis platform for nTDMS currently exists that also integrates search. Here, Proteinaceous is developing and commercializing a new software named ProSight Native to fill this analysis void. In Phase I of the development, a first-of-its-kind platform was introduced for analyzing targeted protein complex data from the classic nTDMS complex-down experiment. The platform offers deconvolution for intact complexes and their dissociated subunits, as well as search for subunit identification and a stoichiometry calculation for complex composition determination. For the Phase II grant, a host of new research will be undertaken to enable a comprehensive platform to be commercialized that features an improved deconvolution algorithm for native proteoforms, the first-ever nTDMS-specific high-throughput search, and robust quantitation workflows for biopharma applications. Major development effort will be spent here on new techniques for nTDMS searches of both proteoforms and complexes, including a multi-pronged approach for scoring automated stoichiometry assignments. Additionally, structural biology elements will be integrated alongside proteoform fragmentation data to bring these important components together and facilitate connections between the two. Lastly, the results will be displayed in an intuitive, structural biology-centric viewer that will make analysis approachable for mass spectrometrists and non-mass spectrometrist alike. In total, ProSight Native will aim to significantly advance nTDMS with these novel features, while also increasing accessibility to the powerful data that can be generated using nTDMS techniques.

项目摘要 天然自上而下质谱法正在继续发展成为一种强大的分析技术， 生成关于蛋白质和蛋白质复合物的天然状态的变革性数据。技术进步 近年来，在质谱仪中的应用促进了nTDMS的快速发展，为以下方面铺平了令人印象深刻的道路： 结构生物学研究和蛋白质治疗学发展。例如，对非共价键的新见解 配体结合和定位可以通过与传统结构互补的nTDMS数据来揭示。 生物学方法，如电子显微镜和NMR。药物开发人员可以将nTDMS应用于研究 临床前和临床环境中的治疗性蛋白质，以了解更多关于存在的修饰和 复合体正在形成。新型蛋白质和蛋白质复合物药物分子的数量不断增加， 每一个都有许多困难的分析和数据分析挑战。在nTDMS的生物信息学方面，进展 在大分子质量测定的算法开发中已经取得了进展;然而，没有完全 nTDMS的特色分析平台目前存在，也集成了搜索。在这里，蛋白质是 开发并商业化一种名为ProSight Native的新软件，以填补这一分析空白。一阶段 该开发是一种首创的平台，用于分析来自 经典的nTDMS复合物下降实验。该平台为完整的复合物及其 解离的亚基，以及寻找亚基鉴定和化学计量计算的复杂 成分测定至于第二阶段拨款，我们会进行一系列新的研究， 一个全面的商业化平台，其特点是改进的反卷积算法， Proteoforms，第一个nTMS特异性高通量搜索，以及强大的定量工作流程， 生物制药应用。主要的开发工作将花在nTDMS搜索的新技术上， 蛋白质和复合物，包括一个多管齐下的方法来评分自动化学计量 分配任务。此外，结构生物学元素将与蛋白质片段化数据一起整合 将这些重要的组成部分结合在一起，并促进两者之间的联系。最后，结果将 以直观的、结构生物学为中心的查看器显示， 光谱测量师和非质谱测量师一样。总的来说，ProSight Native的目标是显著提高 具有这些新颖功能的nTDMS，同时还增加了对可生成的强大数据的可访问性 使用nTDMS技术。