Center for Catalytic Bioscavenger Medical Defense Research - U54

两种蛋白质，人血浆BuChE和重组人BuChE均处于高级开发阶段 作为对抗化学战剂的潜在药物。这些蛋白质反应迅速， 以有效地消除血流中的毒物，但是它们需要相对大的 大量的蛋白质来提供保护。确定一种基于蛋白质的药物的挑战是， 需要更少的材料，同时提供具有增强的用户接受度的优点的改进的保护 不容忽视我们实验室最近的努力已经将人对氧磷酶（PON）鉴定为一种蛋白质 它可以催化所有神经毒剂的水解，作为一种天然存在的血浆酶， 数小时或数天的体内生物利用度。因此，它是一个很好的候选人phrophylactic管理 为恐怖袭击的第一反应者或平民维和部队提供保护 受到不对称的威胁如果是静脉注射的话， 一部分暴露于神经毒剂的平民的治疗性解毒剂。初步 研究显示，这些目标是可行和可以达到的。这样的成本/效益比 药物是这样的，它是一个很好的候选人成功，并有潜力成为第一个在一系列的 新型药物。我们建议使用合理的设计来确定那些对催化活性至关重要的氨基酸， 活性，然后使用定点诱变，增强人PON的天然催化活性， 在五年内创造一个可行的候选人过渡到临床试验。这将 解决在保护平民不受恐怖分子发起的恐怖袭击的国家目标方面的一个关键差距， 化学武器袭击。 目前针对恐怖分子接触化学神经毒剂的医疗保护仅限于接触后 治疗我们将鉴定和开发一种能够提供快速和有效的抗肿瘤药物的人类蛋白质， 长期持久的预防性保护，防止接触化学战神经毒剂。这种药物将 实现向广大民众提供更好的保护， 恐怖分子发动的化学武器袭击

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.