The principal aim of this study is to optimize the efficient and affordable butyrylcholinesterase (BChE) based catalytic scavenger system developed in vitro for treatment of acute organophosphate (OP) intoxication. Currently used oxime and atropine combination therapy is inefficient for treatment of higher exposure OP poisoning due to constant acetylcholinesterase (AChE) reinhibition by excess OP. Novel approaches in therapy based on BChE as stoichiometric scavenger appear prohibitively expensive with a four figure price tag per single application. Conversion of BChE from stoichiometric to catalytic scavenger by combining it with an oxime reactivator has been hampered by lack of efficient BChE reactivators. In our preliminary studies we were able to identify a novel class of superior specific BChE reactivators of distinct nontraditional structural scaffold. Our proposed study deals with optimization of this novel class of reactivators using six step optimization iterative cycle that include detailed kinetic characterization of both reactivation and OP hydrolytic properties of oxime*BChE catalytic scavenger systems in buffer medium, extracorporeal human blood and in vivo in mouse animal model. Results of preliminary studies indicate that BChE in combination with optimized oxime reactivators should completely and rapidly, in a several minute timeframe, hydrolyze OPs in plasma space following exposure to an order of magnitude higher then LD50 OP doses at a fraction of cost of currently developed BChE based stoichiometric scavenger system. The proposed optimized catalytic scavenger system technology will thus enable an effective treatment of large OP intoxicated populations and serve as deterrent to the use of OP based nerve agents as terrorist or combat weapons in closed ventilation systems.
This project will develop optimized, efficient and affordable butyrylcholinesterase based catalytic scavenger system for rapid degradation of toxicants in the plasma space of patients exposed to OP agents.
|Ma?ek Hrvat, Nikolina; Žunec, Suzana; Taylor, Palmer et al. (2016) HI-6 assisted catalytic scavenging of VX by acetylcholinesterase choline binding site mutants. Chem Biol Interact 259:148-153|
|Kovalevsky, Andrey; Blumenthal, Donald K; Cheng, Xiaolin et al. (2016) Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning. Ann N Y Acad Sci 1378:41-49|
|Schmidt, Hayden R; Radi?, Zoran; Taylor, Palmer et al. (2015) Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system. Toxicol Appl Pharmacol 284:197-203|
|Kovarik, Zrinka; Ma?ek Hrvat, Nikolina; Katalini?, Maja et al. (2015) Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes. Chem Res Toxicol 28:1036-44|
|Sit, Rakesh K; Fokin, Valery V; Amitai, Gabriel et al. (2014) Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification. J Med Chem 57:1378-89|
|Radi?, Zoran; Dale, Trevor; Kovarik, Zrinka et al. (2013) Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes. Biochem J 450:231-42|
|Ajami, Dariush; Rebek Jr, Julius (2013) Chemical approaches for detection and destruction of nerve agents. Org Biomol Chem 11:3936-42|