Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma

描述（由申请人提供）：本研究的主要目的是优化体外开发的用于治疗急性有机磷（OP）中毒的高效且经济的基于丁基胆碱酯酶（BChE）的催化清除系统。目前使用的肟和阿托品联合治疗对于高暴露性OP中毒是无效的，因为过量的OP会持续抑制乙酰胆碱酯酶（AChE）。基于BChE作为化学清除剂的新治疗方法似乎过于昂贵，每次应用的价格高达四位数。由于缺乏高效的BChE再活化剂，BChE与肟再活化剂结合从化学计量清除剂转化为催化清除剂一直受到阻碍。在我们的初步研究中，我们能够识别出一类新型的优越的特异性BChE再激活剂，用于不同的非传统结构支架。我们提出的研究涉及这类新型再激活剂的优化，采用六步优化迭代循环，包括在缓冲介质、体外人血和小鼠动物模型中肟*BChE催化清除剂系统的再激活和OP水解性能的详细动力学表征。初步研究结果表明，与目前开发的基于BChE的化学清除系统相比，BChE与优化的肟再活化剂联合使用，在暴露于比LD50高数量级的OP剂量后，可以在几分钟内完全、快速地水解血浆空间中的OPs，而成本只是其一小部分。因此，所提出的优化催化清除系统技术将能够有效治疗大量OP中毒人群，并在封闭通风系统中威慑使用基于OP的神经毒剂作为恐怖分子或战斗武器。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.