Analytical Chemistry

分析化学

• 批准号: 10682311
• 负责人: Christopher Arthur LeClair
• 金额: $ 239.84万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682311
• 关键词: Address; Adopted; Adoption; Affinity; Aging; Analytical Chemistry; Antiviral Agents; Area; Bar Codes; Binding Proteins; Biological; Biological Assay; Biological Markers; Biology; COVID-19 pandemic; COVID-19 treatment; Cells; Chemicals; Chemistry; Collaborations; Collection; Communities; Computers and Advanced Instrumentation; Coronavirus; Custom; Data Analyses; Data Analytics; Data Storage and Retrieval; Detection; Development; Disease; Emerging Technologies; Ensure; Equipment; Equipment and supply inventories; Extramural Activities; Family; Generations; Goals; Health; High Pressure Liquid Chromatography; Hybrids; Industry Standard; Informatics; Intellectual Property; Investigational Drugs; Laboratories; Libraries; Lipids; Liquid Chromatography; Liquid substance; Logistics; Maintenance; Management Information Systems; Manuals; Mass Fragmentography; Mass Spectrum Analysis; Measurement; Mentorship; Metabolism; Methods; Mission; Modality; Monitor; NMR Spectroscopy; National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Disease; Nuclear Magnetic Resonance; Oral; Peptides; Performance; Pharmaceutical Chemistry; Phase; Phenotype; Preparation; Procedures; Process; Productivity; Proteins; Proteomics; Protocols documentation; Publications; Reaction; Reproducibility; Research; Research Project Grants; Research Support; Resolution; Resources; Safety; Sampling; Services; System; Techniques; Technology; Therapeutic; Time; Toxic effect; Translational Research; Validation; Vial device; Vibrational Circular Dichroism; Virus; Workload; analytical method; antiviral drug development; base; coronavirus disease; data acquisition; data management; drug development; drug discovery; end of life; experience; high-throughput drug screening; improved; innovation; instrument; instrumentation; interest; lead optimization; lipidomics; liquid chromatography mass spectrometry; metabolomics; milligram; multiple omics; new technology; novel; operation; pandemic disease; pre-clinical; preclinical development; process optimization; professional atmosphere; programs; screening; screening program; small molecule; success; tool; translational scientist; treatment response

The COVID-19 global pandemic has continued to have an impact on ACC research and support efforts due to modified laboratory operating procedures, as well as a shift to a hybrid work environment. We are still navigating the logistical challenges of providing core analytical chemistry services while maintaining the health and safety of DPI staff. The success of DPI research projects, initiatives, and programs depends on the uninterrupted operation of analytical services and resources, which facilitates forward progress and translational discoveries. Analytical data and analysis must be made promptly available in a convenient format to allow timely and informed decisions regarding the direction or even continuation of projects. To accomplish this, the ACC developed and modified protocols and workflows to handle the increased workload. These efforts have allowed the ACC to maintain involvement in COVID-related projects while also restarting research projects halted during the pandemic, as well as initiate new projects. NCATS has become a key partner in the Antiviral Program for Pandemics (APP), a multi-agency initiative that includes NIAID and BARDA, to accelerate antiviral development through early discovery and preclinical development of safe and effective oral antivirals. The initial priority for the APP is to develop treatments for SARS-CoV-2 and other coronaviruses, with the program expanding to address other virus families with pandemic potential. NCATS will apply its proficiency in drug discovery and development and its cutting-edge technologies to fill critical needs of the APP, such as (i) target validation, (ii) high-throughput screening (HTS) for drug starting points, (iii) medicinal chemistry for lead optimization, and (iv) preclinical, investigational new drug (IND)-enabling development. APP chemists within DPI are tasked with the discovery and development potential small molecule antiviral treatments for a range of viruses that have pandemic potential. In order to meet the increased demand for sample purification and analysis, the ACC needed to improve throughput and expand capabilities through procurement of additional instrumentation and equipment, as well as the application of new technologies. The ACC continues to provide core analytical chemistry services involving the isolation, purification, identification, and analysis of therapeutic modalities for targeted disease states. We are utilizing the Sample Management and Resource Tracking (SMART) Centralized Sample Purification and Processing Platform for the transfer of compounds from Medicinal Chemistry to Compound Management (CoMa) enabling faster turnaround between small molecule synthesis and biological assays. The purification employs semi-preparative liquid chromatography systems utilizing UV- and mass-directed detection and collection to purify a wide range of small molecules and peptides in the milligrams to grams scale. The SMART laboratory information management system (LIMS) continues to be utilized for sample submission, compound purification and processing, sample registration, compound inventory, sample tracking, and data retrieval and management. While these efforts have been highly successful over the past 10 years, the high-performance liquid chromatography (HPLC) instrumentation has seen heavy usage. Therefore, we have procured a replacement preparative purification system, as well as a UPLC-MS system for faster and more efficient sample analysis. To improve upon our sample purification and processing workflow, we have been developing an automated purification platform that will operate as a stand-alone system or an integrated module within the automated laboratory. This innovative system consists of a custom liquid handling platform that incorporates analytical and purification LC instruments into a single automated unit. This will enable replacement of manual steps in workflow with automated protocols as a means of accelerating the drug discovery process. A key aspect of ACC research is the utilization of LCMS analysis throughout all stages of the workflow for reaction monitoring, identity verification, and purity analysis of the desired compounds. To improve efficiency and increase productivity, the ACC has procured the Lab2Lab pneumatic sample transport system, which sends 2D-barcoded minitubes between labs, storage systems, and analytical instrumentation. Chemists located in five labs across two buildings will be able to submit samples directly from their bench for transport to centrally located LCMS instruments near the Analytical Chemistry lab space where analytical measurements are performed. This enables ease of oversight and maintenance, sample tracking capabilities and maximization of instrument usage, and freeing of limited laboratory space. The Lab2Lab system aims to tackle the growing needs of analytical chemistry by streamlining analytical workflows of not just LCMS but also nuclear magnetic resonance (NMR) spectroscopy. The ACC has acquired a Bruker 400 MHz NMR along with the Lab2NMR platform to enable automated NMR operations. The NMR spectrometer outfitted with the Lab2NMR platform is connected to the Lab2Lab system for the transport of vials for automated NMR sample preparation and data acquisition. The Lab2NMR ensures the ACC can seamlessly integrate automated NMR data acquisition and analysis into our workflow and processes. NMR analytical capabilities continue to expand within the ACC through the acquisition of advanced instrumentation and the incorporation of new and emerging techniques in order to detect, identify, quantify, and validate a wide array of therapeutic modalities. We are in the process of replacing aging instrumentation with obsolete technology that has experienced increased malfunctioning as the systems approach their end of life. We have purchased a JEOL 400 MHz NMR for routine open access to the medicinal chemists. The old NMR spectrometer was decommissioned to make space for the new instrumentation. To aid in the discovery phase of drug development, we have been developing our fragment-based screening (FBS) program over several years. NMR-based fragment screening is a powerful approach due its ability to detect very weak ligand-protein binding affinities across a large and diverse chemical space. In anticipation of onboarding a growing number of FBS projects, the ACC has acquired a new fragment library with high chemical diversity to replace our current first-generation fragment library. In collaboration with the ASPIRE program, the ACC continues to develop our automated quantitative NMR (qNMR) platform for concentration determination, purity determination, and reaction analysis. For mass spectrometry (MS), the ACC in collaboration with the Informatics Core (IFX) has been developing a multi-omics analysis platform that will include, but is not limited to proteomics, metabolomics, and lipidomics. Current MS instrumentation in the ACC is primarily configured for routine targeted MS-based studies. We have recently purchased an Agilent LC-QTOF system that will be dedicated to untargeted metabolomics experimentation, which will fulfill an unmet research need at NCATS. Untargeted metabolomic profiling captures a detailed view of the chemical processes underlying cells and is the closest representation of a given phenotype (compared to other omics). Several applications of this instrument include (i) identifying biomarkers of toxicity, treatment response, and diseases, (ii) elucidating biological mechanisms underlying cellular differentiation, disease development, and treatment response, (iii) narrowing down possible compounds to evaluate in assays based on metabolism features. The LC-QTOF system allows the ACC and IFX to expand multi-omic capabilities of NCATS.

由于实验室操作程序的修改以及向混合工作环境的转变，COVID-19 全球大流行继续对 ACC 的研究和支持工作产生影响。我们仍在应对提供核心分析化学服务的后勤挑战，同时维护 DPI 员工的健康和安全。 DPI 研究项目、举措和计划的成功取决于分析服务和资源的不间断运行，这有助于推动进展和转化发现。分析数据和分析必须以方便的格式及时提供，以便就项目的方向甚至继续进行及时、明智的决策。为了实现这一目标，ACC 开发并修改了协议和工作流程来处理增加的工作量。这些努力使 ACC 能够继续参与与新冠病毒相关的项目，同时重新启动大流行期间暂停的研究项目，并启动新项目。 NCATS 已成为流行病抗病毒计划 (APP) 的重要合作伙伴，该计划是一项包括 NIAID 和 BARDA 在内的多机构计划，旨在通过安全有效的口服抗病毒药物的早期发现和临床前开发来加速抗病毒药物的开发。该 APP 的首要任务是开发针对 SARS-CoV-2 和其他冠状病毒的治疗方法，随后该计划将扩展到解决其他具有大流行潜力的病毒家族。 NCATS 将运用其在药物发现和开发方面的专业知识及其尖端技术来满足 APP 的关键需求，例如 (i) 靶标验证，(ii) 药物起始点的高通量筛选 (HTS)，(iii)用于先导化合物优化的药物化学，以及 (iv) 临床前、研究性新药 (IND) 开发。 DPI 内的 APP 化学家的任务是发现和开发针对一系列具有大流行潜力的病毒的潜在小分子抗病毒治疗方法。为了满足样品纯化和分析日益增长的需求，ACC 需要通过采购额外的仪器和设备以及应用新技术来提高通量并扩展能力。 ACC 继续提供核心分析化学服务，涉及针对目标疾病状态的治疗方式的分离、纯化、鉴定和分析。我们正在利用样品管理和资源跟踪 (SMART) 集中样品纯化和处理平台将化合物从药物化学转移到化合物管理 (CoMa)，从而实现小分子合成和生物测定之间的更快周转。纯化采用半制备型液相色谱系统，利用紫外和质量定向检测和收集来纯化毫克至克级的各种小分子和肽。 SMART 实验室信息管理系统 (LIMS) 继续用于样品提交、化合物纯化和处理、样品注册、化合物库存、样品跟踪以及数据检索和管理。虽然这些努力在过去 10 年中取得了巨大成功，但高效液相色谱 (HPLC) 仪器的使用率却很高。因此，我们采购了备用制备纯化系统以及 UPLC-MS 系统，以实现更快、更高效的样品分析。为了改进我们的样品纯化和处理工作流程，我们一直在开发一个自动化纯化平台，该平台将作为独立系统或自动化实验室内的集成模块运行。该创新系统由定制液体处理平台组成，该平台将分析和纯化 LC 仪器整合到一个自动化单元中。这将使工作流程中的手动步骤替换为自动化协议，作为加速药物发现过程的一种手段。 ACC 研究的一个关键方面是在工作流程的所有阶段利用 LCMS 分析来进行反应监测、身份验证和所需化合物的纯度分析。为了提高效率和生产率，ACC 采购了 Lab2Lab 气动样品传输系统，该系统可在实验室、存储系统和分析仪器之间发送二维条形码微型管。位于两座大楼的五个实验室的化学家将能够直接从他们的工作台提交样品，以便运输到分析化学实验室空间附近的中央 LCMS 仪器，在那里进行分析测量。这使得监督和维护变得容易，样品跟踪能力和仪器使用最大化，并释放有限的实验室空间。 Lab2Lab 系统旨在通过简化 LCMS 和核磁共振 (NMR) 光谱的分析工作流程来满足分析化学日益增长的需求。 ACC 购买了 Bruker 400 MHz NMR 以及 Lab2NMR 平台，以实现自动化 NMR 操作。配备 Lab2NMR 平台的 NMR 波谱仪连接到 Lab2Lab 系统，用于运输小瓶以进行自动化 NMR 样品制备和数据采集。 Lab2NMR 确保 ACC 能够将自动化 NMR 数据采集和分析无缝集成到我们的工作流程和流程中。 通过购买先进仪器并采用新兴技术，核磁共振分析能力在 ACC 内不断扩展，以检测、识别、量化和验证各种治疗方式。我们正在用过时的技术更换老化的仪器，随着系统接近使用寿命，这些技术的故障会增加。我们购买了 JEOL 400 MHz NMR，用于对药物化学家进行常规开放访问。旧的核磁共振波谱仪已退役，为新仪器腾出空间。为了帮助药物开发的发现阶段，我们多年来一直在开发基于片段的筛选 (FBS) 计划。基于 NMR 的片段筛选是一种强大的方法，因为它能够在大而多样化的化学空间中检测非常弱的配体-蛋白质结合亲和力。由于预计将有越来越多的 FBS 项目加入，ACC 获得了一个具有高化学多样性的新片段库，以取代我们当前的第一代片段库。 ACC 与 ASPIRE 计划合作，继续开发用于浓度测定、纯度测定和反应分析的自动定量 NMR (qNMR) 平台。 对于质谱 (MS)，ACC 与信息学核心 (IFX) 合​​作一直在开发多组学分析平台，其中包括但不限于蛋白质组学、代谢组学和脂质组学。 ACC 中当前的 MS 仪器主要配置用于基于 MS 的常规靶向研究。我们最近购买了一套安捷伦 LC-QTOF 系统，该系统将专用于非靶向代谢组学实验，这将满足 NCATS 未满足的研究需求。非靶向代谢组学分析捕获了细胞底层化学过程的详细视图，并且是给定表型的最接近的表示（与其他组学相比）。该仪器的几个应用包括（i）识别毒性、治疗反应和疾病的生物标志物，（ii）阐明细胞分化、疾病发展和治疗反应的生物学机制，（iii）缩小可能的化合物范围，以在基于代谢特征。 LC-QTOF 系统允许 ACC 和 IFX 扩展 NCATS 的多组学能力。