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）中毒的高效且经济实惠的基于丁酰胆碱酯酶（BChE）的催化清除剂系统。目前使用的肟和阿托品联合治疗是低效的治疗高暴露OP中毒由于恒定的乙酰胆碱酯酶（AChE）reinstrumented过量OP。新的方法在治疗的基础上BChE作为化学计量清除剂出现四位数的价格标签，每一个单一的应用程序昂贵得令人望而却步。通过将BChE与肟再活化剂结合将BChE从化学计量转化为催化清除剂，由于缺乏有效的BChE再活化剂而受到阻碍。在我们的初步研究中，我们能够确定一个新的类别的上级特定的BChE重激活剂的独特的非传统的结构支架。我们提出的研究涉及使用六步优化迭代循环，包括详细的动力学特性的再活化和OP水解性能的肟 *BChE催化清除剂系统在缓冲介质中，体外人血和在体内的小鼠动物模型中的这类新型的再活化剂的优化。初步研究的结果表明，BChE与优化的肟再活化剂的组合应在几分钟的时间内完全和快速地水解暴露于高于LD 50 OP剂量的数量级后的血浆空间中的OP，其成本仅为目前开发的基于BChE的化学计量清除剂系统的一小部分。因此，所提出的优化催化清除剂系统技术将能够有效地治疗大OP中毒人群，并作为威慑使用OP为基础的神经毒剂作为恐怖分子或战斗武器在封闭的通风系统。 公共卫生相关性：该项目将开发优化的、有效的和负担得起的基于丁酰胆碱酯酶的催化清除剂系统，用于快速降解暴露于OP制剂的患者血浆空间中的毒物。

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.