Core A: Analytical and Medicinal Chemistry Core

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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.