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CounterACT卓越中心的总体目标是识别和推进小说 治疗策略，当作为现场标准治疗（SOC）的辅助治疗时， 有机磷（OP）中毒，将减轻发作和/或严重性的长期，不良的神经系统疾病 后果目前的医学对策，包括毒蕈碱受体拮抗剂，阿托品， 与肟结合，以重新激活乙酰胆碱酯酶和苯二氮卓以终止癫痫持续状态， 不能充分防止自发性复发性癫痫发作（SRS）和认知功能障碍的发生。 除非在暴露后的前15分钟内给药，否则不会出现缺陷。因此，迫切需要查明 新的治疗策略可以在暴露后的延迟时间部署以减轻慢性， 急性OP中毒的不良神经系统后遗症。还迫切需要确定可量化和 预测性生物标志物，其适合于评估潜在的治疗剂并且允许预测 患者发生持续性癫痫发作和认知功能障碍的风险增加， 大多数人从接触后治疗中受益。 分析和药物化学核心（核心A）将作为中心的一个组成部分， 支持并与所有三个项目和神经成像核心合作。在总体上支持整个 中心，核心A将进行质量控制，并确认所有商业获得的密钥的同一性和纯度 化学资源和威胁剂二异丙基氟磷酸盐（DFP）。如有必要，化合物将 在释放到项目之前进行内部纯化。核心A将通过开发流动资金来进一步支持项目 色谱-质谱法（LC/MS）用于检测抗癫痫药物，抗癫痫药物， 炎症和神经保护剂及其代谢产物，并产生药代动力学 数据，以告知剂量选择并证明靶点接合。核心A将利用其药物化学 根据项目的要求，合成小分子探针和潜在的新疗法的专业知识。 此外，核心A将与项目密切合作，确定和量化生物标志物， 癫痫发作活动、神经炎症和血脑屏障通透性的变化以及 潜在的治疗方法核心的监督和管理将由核心负责人Heike Wulff博士提供， 加州大学戴维斯分校药理学教授，在药理学和药物化学方面具有广泛的专业知识; 核心联合负责人，Jun Yang，博士，加州大学戴维斯分校研究科学家，在质谱方面拥有丰富的专业知识 以及全局和靶向代谢组学，特别是脂质介质。通过提供分析和医学 化学专业知识，以及探针和试剂设计，化学资源验证，生物标志物 核心A将确保一致性、科学严谨性、效率和 加州大学戴维斯分校反ACT中心项目的研究重现性。