Two proteins, human plasma BuChE, and a recombinant human BuChE are both in advanced development as potential prophylacitcs for proteting aginst chemical warfare agents. These proteins react rapidly and stoiciometrically to effectively scavenge the poisons in the blood stream but they require relatively large amounts of protein to provide protection. The challenge of identifying a protein based drug that would require less material while providing improved protection with the advantage of enhanced user acceptance cannot be ignored. Recent efforts in our laboratory have identified human paraoxonase (PON) as a protein that can catalyze the hydrolysis of all nerve agents and as a naturally occuring plasma enzyme should have an in vivo bioavailability of hours or days. As such it is an excellent candidate for phrophylactic administration to provide protection for first responders to a terorist attack or military forces in a civilian peacekeeping setting subject to an asymmetric threat. If it were administered intravenously it could also serve as a rapid-onset therapeutic antidote to a segment of the civilian popuation exposed to nerve agents. Preliminary studies have shown that these objectives are both feasible and obtainable. The cost/benefit ratio of such a drug is such that it is an excellent candidate for success and has the potential to be the first in a series of a novel class of drugs. We propose to use rational design to identify those amino acids critical for cataltyic activity and then, using site directe mutagenesis, enhance the native catalytic activity of human PON to create a viable candidate for transition to advancement to clinical trials within a five year period. This will address a critical gap in the national goal of protecting the civilian population against a terrorist-initiated chemical weapons attack. Current medical protection against chemical nerve agent exposure by terrorists is limited to post exposure treatment. We will identify and develop for clinical testing a human protein capable of providing rapid and long lasting prophylactic protection against exposure to chemical warfare nerve agents. Such a drug will address the critical national goal of providing improved protection to the general population against a terrorist-initiated chemical weapons attack.

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 (ZNS1-SRB-R (23))
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Jett, David A
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U.S. Army Medical Research Institute Chem Def
Aberdeen Proving Ground
United States
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Ashani, Yacov; Leader, Haim; Aggarwal, Nidhi et al. (2016) In vitro evaluation of the catalytic activity of paraoxonases and phosphotriesterases predicts the enzyme circulatory levels required for in vivo protection against organophosphate intoxications. Chem Biol Interact 259:252-256
Smith, Carl D; Wright, Linnzi K M; Garcia, Gregory E et al. (2015) Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle. Toxicol Appl Pharmacol 287:253-7
Ben-David, Moshe; Sussman, Joel L; Maxwell, Christopher I et al. (2015) Catalytic stimulation by restrained active-site floppiness--the case of high density lipoprotein-bound serum paraoxonase-1. J Mol Biol 427:1359-1374
Magliery, Thomas J (2015) Protein stability: computation, sequence statistics, and new experimental methods. Curr Opin Struct Biol 33:161-8
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
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
Dwyer, Mary; Javor, Sacha; Ryan, Daniel A et al. (2014) Novel human butyrylcholinesterase variants: toward organophosphonate detoxication. Biochemistry 53:4476-87
Li, Bin; Duysen, Ellen G; Froment, Marie-Thérèse et al. (2013) Polyclonal antibody to soman-tyrosine. Chem Res Toxicol 26:584-92
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
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

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