The goal of the Organophosphorus Nerve Agent Testing (ONAT) Core, a component of the Center for Catalytic Bioscavenger Medical Defense Research, is to test the mutant enzymes produced by other Research Projects in the Center for in vitro and in vivo efficacy against organophosphorus (OP) nerve agents. The results from this testing will contribute directly to the development of a pretreatment that offers complete protection from poisoning by OPs. The core is located at the US Army Medical Research Institute of Chemical Defense, a singular national resource with a highly trained staff of scientists supported by safety, surety, and environmental specialists who ensure regulatory compliance of experiments involving highly toxic surety agents such as OP nerve agents. The mission of the USAMRICD is the development of medical countermeasures against chemical weapons, which is precisely aligned with the mission of the CounterACT initiative. The ONAT core is uniquely positioned to assess the function of anti-OP bioscavengers against bona fide nerve agents;the use of these highly toxic agents is restricted to a very limited number of research facilities worldwide. The tests to be conducted by the core will include characterization of the OP nerve agent reactivity, specificity, and stereoselectivity of candidate bioscavenger enzymes using a combination of colorimetric, calorimetric, and gas chromatographic/mass spectroscopy approaches. The capacity of different enzymes to persist in the circulation of a model test animal, and the protection from OP toxicity afforded by these enzymes will also be evaluated. The multidisciplinary approach of the ONAT core to assay development and efficacy testing will support the development of a 'next generation'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 is important that the USAMRICD, and in particular the PI of the Center as well as the PI for this core component, have experience in both basic science and in early product development, meaning attention will constantly 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.

Public Health Relevance

The goal of the CounterACT program is to create new ways to protect ourselves from toxic chemicals like OP nerve agents. The goal of this core proposal is to test how well these new approaches defend against highly toxic nerve agents. Without the testing that will be conducted by this core, which is unique in its access to OP nerve agents, there will be no way to measure the effectiveness of these new approaches.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1-MDCN-J)
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U.S. Army Medical Research Institute Chem Def
Aberdeen Proving Ground
United States
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Dwyer, Mary; Javor, Sacha; Ryan, Daniel A et al. (2014) Novel human butyrylcholinesterase variants: toward organophosphonate detoxication. Biochemistry 53:4476-87
Rockah-Shmuel, Liat; Tawfik, Dan S; Goldsmith, Moshe (2014) Generating targeted libraries by the combinatorial incorporation of synthetic oligonucleotides during gene shuffling (ISOR). Methods Mol Biol 1179:129-37
Schneider, Jeannine D; Castilho, Alexandra; Neumann, Laura et al. (2014) Expression of human butyrylcholinesterase with an engineered glycosylation profile resembling the plasma-derived orthologue. Biotechnol J 9:501-10
Jiang, Wei; Cashman, John R; Nachon, Florian et al. (2013) Mass spectrometry method to identify aging pathways of Sp- and Rp-tabun adducts on human butyrylcholinesterase based on the acid labile P-N bond. Toxicol Sci 132:390-8
Ben-David, Moshe; Wieczorek, Grzegorz; Elias, Mikael et al. (2013) Catalytic metal ion rearrangements underline promiscuity and evolvability of a metalloenzyme. J Mol Biol 425:1028-38
Goldsmith, Moshe; Tawfik, Dan S (2013) Enzyme engineering by targeted libraries. Methods Enzymol 523:257-83
Luechapanichkul, Rinrada; Chen, Xianwen; Taha, Hashem A et al. (2013) Specificity profiling of dual specificity phosphatase vaccinia VH1-related (VHR) reveals two distinct substrate binding modes. J Biol Chem 288:6498-510
Goldsmith, Moshe; Ashani, Yacov; Simo, Yair et al. (2012) Evolved stereoselective hydrolases for broad-spectrum G-type nerve agent detoxification. Chem Biol 19:456-66
Ben-David, Moshe; Elias, Mikael; Filippi, Jean-Jacques et al. (2012) Catalytic versatility and backups in enzyme active sites: the case of serum paraoxonase 1. J Mol Biol 418:181-96
Styslinger, Thomas J; Zhang, Ning; Bhatt, Veer S et al. (2012) Site-selective glycosylation of hemoglobin with variable molecular weight oligosaccharides: potential alternative to PEGylation. J Am Chem Soc 134:7507-15

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