Core A: Analytical and Medicinal Chemistry Core

核心 A：分析和药物化学核心

• 批准号: 10684074
• 负责人: HEIKE WULFF
• 金额: $ 27.2万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684074
• 关键词: Acetylcholinesterase; Acute; Analytical Chemistry; Anti-Inflammatory Agents; Anticonvulsants; Atropine; Benzodiazepines; Biological Assay; Biological Markers; Brain; Calpain; Chronic; Cognitive deficits; Collaborations; Cyclooxygenase Inhibitors; Data; Dedications; Detection; Development; Doctor of Philosophy; Dose; Drug Kinetics; Ensure; Enzyme-Linked Immunosorbent Assay; Epilepsy; Epoxide hydrolase; Exposure to; Formulation; Goals; Immunoassay; Impaired cognition; Intoxication; Isoflurophate; Lead; Mass Fragmentography; Mass Spectrum Analysis; Measures; Monitor; Muscarinic Acetylcholine Receptor; Neurologic; Neurons; Neuroprotective Agents; Organophosphates; Oximes; Patients; Penetration; Pharmaceutical Chemistry; Pharmacology; Plasma; Plasminogen Activator Inhibitor 1; Quality Control; Reagent; Recurrence; Reproducibility; Research; Risk; STAT3 gene; Scientist; Seizures; Services; Severities; Status Epilepticus; Therapeutic; Tissues; Transforming Growth Factor beta Receptors; Work; antagonist; biomarker identification; blood-brain barrier permeabilization; calcium-activated potassium channel small-conductance; chemical resource; design; detection method; endoplasmic reticulum stress; improved; inhibitor; lipid mediator; liquid chromatography mass spectrometry; medical countermeasure; metabolomics; nanobodies; neuroimaging; neuroinflammation; novel therapeutic intervention; novel therapeutics; pharmacokinetics and pharmacodynamics; physical property; predictive marker; professor; reagent testing; small molecule; stability testing; standard of care; therapeutic candidate

Project Summary – Analytical and Medicinal Chemistry (AMC) Core – Core A The overall goal of the new UC Davis CounterACT Center of Excellence is to identify and advance novel therapeutic strategies that, when administered as an adjunct to in-field standard-of-care (SOC) for acute organophosphate (OP) intoxication, will mitigate the onset and/or severity of long-term, adverse neurological consequences. Current medical countermeasures, which include the muscarinic receptor antagonist, atropine, combined with an oxime, to reactivate acetylcholinesterase and a benzodiazepine to terminate status epilepticus, do not sufficiently protect against the development of spontaneous recurrent seizures (SRS) and cognitive deficits unless administered in the first 15-min after exposure. Therefore, there exists an urgent need to identify novel therapeutic strategies that can be deployed at delayed times post-exposure to mitigate the chronic, adverse neurological sequelae of acute OP intoxication. There is also a critical need to identify quantifiable and predictive biomarkers that are suitable for evaluating potential therapeutics and that allow prediction of which patients are at increased risk of developing persistent seizure disorders and cognitive dysfunction and would most benefit from post-exposure treatment. The Analytical and Medicinal Chemistry Core (Core A) will function as an integral component of the Center by supporting and collaborating with all three Projects and the Neuroimaging Core. In general support of the entire Center, Core A will perform quality control and confirm the identity and purity of all commercially obtained key chemical resources and the threat agent diisopropylfluorophosphate (DFP). If necessary, compounds will be purified in-house before release to the Projects. Core A will further support the Projects by developing liquid chromatography–mass spectrometry (LC/MS) methods for the detection of antiseizure drugs, anti- inflammatories and neuroprotectants and their metabolites in plasma and tissues, and generate pharmacokinetic data to inform dose selection and demonstrate target engagement. Core A will use its medicinal chemistry expertise to synthesize small molecule probes and potential novel therapeutics as required by the Projects. Additionally, Core A will closely work with the Projects on the identification and quantification of biomarkers for seizure activity, neuroinflammation and changes in blood-brain-barrier permeability and their amelioration by potential therapeutics. Oversight and management of the Core will be provided by Core Lead, Heike Wulff, PhD, Professor of Pharmacology at UC Davis with broad expertise in pharmacology and medicinal chemistry; and Core Co-Lead, Jun Yang, PhD, Research Scientist at UC Davis, with extensive expertise in mass spectrometry and both global and targeted metabolomics, particularly lipid mediators. By providing analytical and medicinal chemistry expertise, and dedicated services of probe and reagent design, chemical resource verification, biomarker identification/detection and PK/PD analysis, Core A will ensure consistency, scientific rigor, efficiency, and reproducibility in research across the Projects of the UC Davis CounterACT Center.

项目摘要 - 分析和药物化学（AMC）核心 - 核心A 新的加州大学戴维斯分校抵抗卓越中心的总体目标是识别和推进小说 治疗策略，当作为急性现场护理（SOC）的辅助策略时 有机磷酸盐（OP）中毒将减轻长期，不良神经系统的发作和/或严重程度 结果。当前的医学对策，包括毒蕈碱受体拮抗剂阿托品， 与氧气相结合，重新激活乙酰胆碱酯酶和苯二氮卓类化酶以终止癫痫持续状态， 不要充分防止发起复发性癫痫发作（SRS）和认知的发展 缺陷，除非在暴露后的前15分钟内给药。因此，迫切需要识别 新颖的理论策略可以在暴露后延迟部署以减轻慢性， 不良神经后遗症的后遗症。还需要确定可量化和 适合评估潜在疗法的预测生物标志物，并允许预测 患者患有持续性癫痫发作和认知功能障碍的风险增加，并且会增加 暴露后治疗中的最大好处。 分析和药物化学核心（核心A）将通过 支持和合作与所有三个项目和神经影像核心。一般支持整个 中心，核心A将执行质量控制并确认所有商业获得的密钥的身份和纯度 化学资源和威胁剂二异丙氟磷酸酯（DFP）。如有必要，化合物将是 在发布项目之前，内部纯化。核心A将通过开发液体进一步支持项目 色谱 - 质谱法（LC/MS）方法，用于检测抗性药物，抗抗性药物 炎症和神经保护剂及其在血浆和组织中的代谢产物，并产生药代动力学 数据以告知剂量选择并证明目标参与。核心A将使用其医学化学 根据项目所需的需要综合小分子问题和潜在的新型疗法的专业知识。 此外，核心A将与这些项目密切合作，以识别和量化生物标志物的 癫痫活性，神经炎症和血脑屏障渗透性的变化及其通过 潜在的治疗学。核心的监督和管理将由核心主角Heike Wulff博士提供 加州大学戴维斯分校的药理学教授，在药理学和医学化学方面拥有广泛的专业知识；和 Core Coe Lead，Jun Yang，PhD，UC Davis的研究科学家，具有广泛的质谱专业知识 以及全球和有针对性的代谢组学，尤其是脂质介质。通过提供分析和医学 化学专业知识，以及探针和试剂设计的专门服务，化学资源验证，生物标志物 识别/检测和PK/PD分析，核心A将确保一致性，科学严格，效率和 加州大学戴维斯分校抵消中心的项目的研究可重复性。