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新颖的 治疗策略，当作为现场标准护理（SOC）的辅助手段时，针对急性 有机磷（OP）中毒，将减轻长期不良神经系统症状的发作和/或严重程度 目前的医学对策，包括毒蕈碱受体拮抗剂阿托品， 与肟结合，重新激活乙酰胆碱酯酶和苯二氮卓类药物，以终止癫痫持续状态， 不能充分预防自发性复发性癫痫发作（SRS）和认知障碍的发生 除非在暴露后的前 15 分钟内给药，否则会出现缺陷，因此，迫切需要确定。 可以在暴露后延迟时间部署的新颖治疗策略，以减轻慢性、 急性 OP 中毒的不良神经后遗症也迫切需要确定可量化和可量化的结果。 适合评估潜在疗法并允许预测哪些疗法的预测生物标志物 患者出现持续性癫痫症和认知功能障碍的风险增加，并且 大多数受益于暴露后治疗。 分析和药物化学核心（核心 A）将作为该中心的一个组成部分 支持所有三个项目和神经影像核心并与之合作 总体支持整个项目。 中心，Core 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基氟磷酸盐（DFP） 如有必要，将进行化合物。 在释放到项目之前进行内部纯化，核心 A 将通过开发液体进一步支持项目。 色谱-质谱 (LC/MS) 方法用于检测抗惊厥药物、抗癫痫药物 血浆和组织中的炎症和神经保护剂及其代谢物，并产生药代动力学 核心 A 将使用其药物化学数据来指导剂量选择并证明目标参与度。 根据项目要求合成小分子探针和潜在治疗小说的专业知识。 此外，核心 A 将与项目密切合作，识别和量化生物标志物 癫痫活动、神经炎症和血脑屏障通透性的变化及其改善 潜在的治疗方法将由核心负责人 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拥有广泛的专业知识； 核心联合负责人，杨俊博士，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，特别是脂质介质的分析提供和药物。 化学专业知识，以及探针和试剂设计、化学资源验证、生物标志物的专门服务 鉴定/检测和 PK/PD 分析，核心 A 将确保一致性、科学性、效率和 加州大学戴维斯分校 CounterACT 中心各项目研究的可重复性。