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Principal Investigator: Christopher Arthur LeClair
Organization: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
Fiscal Year: 2024
Award: $2,962,787
Funding agency: National Center for Advancing Translational Sciences
The ACC continued to navigate the logistical challenge of providing core analytical chemistry services to DPI researchers within the framework of the current hybrid work environment. To accommodate the varied onsite and telework schedules of DPI staff, ACC team members worked together to ensure the continuous operability of all service lines and fulfillment of all responsibilities to sustain productivity. The ACC successfully maintained resources and provided analytical support for scientists across the 3 DPI scientific branches (ETB, TDB, and CGB). We also continued to maintain and build collaborations with internal and external partners for a variety of research projects. Even with the end of the COVID pandemic, the ACC has maintained involvement in COVID-related projects primarily through support of the Antiviral Program for Pandemics (APP) team whose mission is 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. APP chemists within DPI are tasked with the discovery and development of potential small molecule antiviral treatments for a range of viruses that have pandemic potential.
The ACC emphasizes training and mentorship as part of efforts to develop the next generation of translational scientists. Career development of both trainees and staff is a significant priority for the ACC where they will acquire and expand (i) specialized knowledge in their focus area of analytical chemistry, (ii) education in diverse techniques, methods, and procedures, (iii) collaborative experience, and (iv) dissemination of research. It is our goal to provide trainees with directly applicable knowledge and hands-on experience making them outstanding scientists who are highly competitive in the next stages of their career path. We onboarded a postdoctoral IRTA fellow focused in mass spectrometry and extended the appointment of a postbaccalaureate IRTA fellow performing NMR spectroscopy research. We also hired a computer scientist to upgrade our SMART laboratory information management system (LIMS) and facilitate integration of analytical instrumentation for better data acquisition and management. Staff and trainees are encouraged to annually attend scientific conferences, meetings, and/or workshops specializing in topics pertinent to the NCATS mission. This allows them to learn of the latest advances in analytical chemistry, as well as present their work to the larger scientific community. ACC scientists presented their research at a number of conferences and meetings where they were authors on 18 posters and 8 presentations. Members of the ACC were co-authors on 6 peer-reviewed publications where we provided experimentation, analysis, and subject matter expertise in the areas of mass spectrometry, high-throughput chemical and biological screening, proteomics, NMR spectroscopy, chiral chromatography, and VCD spectroscopy.
Utilizing the Sample Management and Resource Tracking (SMART) Centralized Sample Purification and Processing Platform, the ACC purified, isolated, identified, and analyzed a wide array of chemical modalities as part of drug discovery efforts. The purification workflow 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. This process for the rapid progression of compounds from Medicinal Chemistry to Compound Management (CoMa) has an average 5-day cycle time and resulted in >3,900 new compounds synthesized by DPI chemistry being added to the NCATS compound library. In coordination with the NCATS Facilities Team, the ACC installed a robotic rail arm that will connect various instruments and equipment utilized with the processing platform. This will create a more integrated automated workflow to improve efficiency and productivity for projects requiring purification of synthesized compounds.
We completed the installation and calibration of instrumentation, which included an Agilent LCMS for connection to an SPT Labtech Lab2Lab pneumatic tubing system, a Waters UPC2-QDa supercritical fluid chromatography (SFC) instrument that will provide additional separation capabilities, and a Covaris R230 Adaptive Focused Acoustics (AFA) instrument to enable 384-well high-throughput processing of various biological materials (e.g., cells, tissue, serum, nematode, etc.), which will be integrated into the ACC automated high-throughput MS sample preparation workflow. We continued to integrate and expand the Lab2Lab system by acquiring additional sample Sender units for the ASPIRE automated chemistry lab, as well as Receivers for the ChemSpeed automated chemistry platform and the Lab2NMR system.
The ACC and NCATS Facilities Team completed the design of a new NMR lab, which has been approved by GSA and construction will begin late FY24/early FY25. As part of the overall NMR Lab relocation and renovation, the ACC and NCATS Facilities Team coordinated the decommission and storage of a Bruker 400 MHz NMR and aided the Chemistry and Synthesis Center, NHLBI with the installation of a Bruker 500 MHz NMR. The ACC and ASPIRE continue to develop an automated quantitative NMR (qNMR) platform from sample preparation to data acquisition to data analysis. This innovative platform will enable fast and efficient determination of sample concentration, purity analysis, and mixture identification. The technology is being used to validate an automated NMR sample preparation workflow. We continue to develop and validate an NMR-based fragment screening program having successfully obtained reference data of the chemically diverse fragment library. This NMR method is being used to perform ligand-protein binding studies to identify reversible small molecule binders of lecithin-cholesterol acyltransferase (LCAT), an enzyme involved in the clearance of excess cholesterol.
The ACC has performed >82,000 sample injections as part of numerous Agilent RapidFire MS-based high-throughput assays providing excellent data that has identified small molecule inhibitors and activators for a number of disease-related protein targets. A collaboration between ACC, ETB, NIDDK, and University of Maryland School of Medicine identified auranofin, a gold-based compound approved for the treatment of rheumatoid arthritis, as the first reported enhancer of UBA1 activity. This discovery is not only the first demonstration that UBA1 activity can be enhanced by a small-molecule drug but also identifies auranofin as an invaluable tool for UBA1 research and therapeutic exploration. Auranofin has the promise of repurposing as a therapeutic candidate to treat rare conditions caused by faulty or inactive UBA1. The ACC in collaboration with ChemTech developed an Activity-Based Proteomic Profiling (ABPP) platform for kinase selectivity profiling for use by DPI researchers and collaborative partners. In addition to determining the selectivity of kinase inhibitors, the discovery of off-target activity could be exploited to identify novel small molecule candidates for other therapeutic targets. The ABPP platform is highly adaptable enabling proteomics screening for not just kinases but any class of proteins with a selective probe.
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Retrieval><Detection><Development><Disease><Disorder><Drugs><EXTMR><Education><Educational aspects><Educational workshop><Emergent Technologies><Emerging Technologies><Enhancers><Ensure><Enzyme Gene><Enzymes><Equipment><Equipment and supply inventories><Extramural><Extramural Activities><Family><GC MS><GCMS><Gas-Liquid-Mass Spectrometry Chromatography><Goals><Gold><HPLC><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><High Throughput Assay><Hybrids><Hydrogen Oxide><Industry Standard><Injections><Intellectual Property><Inventory><Investigators><Kinases><Knowledge><LC/MS><LCAT><Laboratories><Learning><Lecithin Acyltransferase><Lecithin Cholesterol Acyltransferase><Libraries><Ligand Binding Protein><Ligand Binding Protein Gene><Lipids><Liquid Chromatography><Management Information Systems><Maryland><Mass Fragmentographies><Mass Fragmentography><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass 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