The goal of the Organophosphorus Nerve Agent Testing (ONAT) Core, a component of the Center forCatalytic Bioscavenger Medical Defense Research, is to test the mutant enzymes produced by otherResearch Projects in the Center for in vitro and in vivo efficacy against organophosphorus (OP) nerveagents. The results from this testing will contribute directly to the development of a pretreatment that offerscomplete protection from poisoning by OPs. The core is located at the US Army Medical Research Instituteof Chemical Defense, a singular national resource with a highly trained staff of scientists supported bysafety, surety, and environmental specialists who ensure regulatory compliance of experiments involvinghighly toxic surety agents such as OP nerve agents. The mission of the USAMRICD is the development ofmedical countermeasures against chemical weapons, which is precisely aligned with the mission of theCounterACT initiative. The ONAT core is uniquely positioned to assess the function of anti-OPbioscavengers against bona fide nerve agents; the use of these highly toxic agents is restricted to a verylimited number of research facilities worldwide. The tests to be conducted by the core will includecharacterization of the OP nerve agent reactivity, specificity, and stereoselectivity of candidate bioscavengerenzymes using a combination of colorimetric, calorimetric, and gas chromatographic/mass spectroscopyapproaches. The capacity of different enzymes to persist in the circulation of a model test animal, and theprotection from OP toxicity afforded by these enzymes will also be evaluated. The multidisciplinary approachof the ONAT core to assay development and efficacy testing will support the development of a 'nextgeneration' bioscavenger molecule with the potential to bind and destroy OP nerve agents in the blood,before they distribute to the brain, central nervous system, and other toxic targets. In this regard it isimportant that the USAMRICD, and in particular the PI of the Center as well as the PI for this corecomponent, have experience in both basic science and in early product development, meaning attention willconstantly remain focused on not only the scientific issues, but also on the requirements to develop a novel,protein based drug product that will protect against the otherwise toxic effects of OP nerve agent exposure.The goal of the CounterACT program is to create new ways to protect ourselves from toxic chemicals likeOP nerve agents. The goal of this core proposal is to test how well these new approaches defend againsthighly toxic nerve agents. Without the testing that will be conducted by this core, which is unique in itsaccess to OP nerve agents, there will be no way to measure the effectiveness of these new approaches.
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