Center for Catalytic Bioscavenger Medical Defense Research - U54

两种蛋白质，人血浆BuChE和重组人BuChE都处于后期开发阶段 作为保护化学战剂的潜在防腐剂。这些蛋白质反应迅速， 化学计量学上有效地清除血流中的毒物，但它们需要相对较大的 提供保护的蛋白质含量。识别一种基于蛋白质的药物将是一项挑战 需要的材料更少，同时提供更好的保护，用户接受度更高 不能被忽视。我们实验室最近的工作已将人对氧磷酶(PON)鉴定为一种蛋白质 它可以催化所有神经毒剂的水解，作为一种自然产生的血浆酶，它应该具有 体内生物利用度为数小时或数天。因此，它是一种很好的预防给药方案。 在平民维和行动中为恐怖袭击的第一反应人员或军事力量提供保护 受到不对称威胁的环境。如果静脉给药，它也可能是一种快速发作的 对暴露于神经毒剂的部分平民人口的治疗解毒剂。初步 研究表明，这些目标既是可行的，也是可以实现的。这样的成本/收益比 药物是这样的，它是一个极好的成功候选者，并有可能成为一系列 新奇的药物类别。我们建议使用合理的设计来鉴定那些对类固醇至关重要的氨基酸。 活性，然后利用定点突变，增强人PON的天然催化活性 为在五年内过渡到临床试验创造一个可行的候选者。这将是 解决保护平民免遭恐怖分子袭击的国家目标中的重大差距 化学武器袭击。 目前针对恐怖分子接触化学神经毒剂的医学保护仅限于接触后 治疗。我们将确定并开发一种用于临床测试的人类蛋白，该蛋白能够提供快速和 长期预防暴露于化学战神经毒剂的防护。这样的药物会 解决关键的国家目标，即改善对普通民众的保护，防止 恐怖分子发起的化学武器袭击。

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.