Center for Catalytic Bioscavenger Medical Defense Research - U54

催化生物清除剂医疗防御研究中心 - U54

• 批准号: 7920104
• 负责人: DAVID E LENZ
• 金额: $ 220.63万
• 依托单位: U.S. ARMY MEDICAL RESEARCH INST CHEM DEF
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920104
• 关键词: Center; Catalytic; Bioscavenger; Medical; Defense

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.

两种蛋白质，人血浆 BuChE 和重组人 BuChE 均处于高级开发阶段 作为防护化学战剂的潜在预防剂。这些蛋白质反应迅速， 按化学计量有效清除血液中的毒物，但需要相对较大的 一定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 需要更少的材料，同时提供更好的保护，具有增强用户接受度的优点 不容忽视。我们实验室最近的工作已确定人类对氧磷酶 (PON) 是一种蛋白质 可以催化所有神经毒剂的水解，并且作为天然存在的血浆酶应该具有 体内生物利用度为数小时或数天。因此，它是预防性给药的绝佳候选者 为恐怖袭击的急救人员或民间维和部队提供保护 设置受到不对称威胁。如果通过静脉注射，它也可以作为快速起效的药物。 为部分接触神经毒剂的平民提供治疗性解毒剂。初步的 研究表明，这些目标都是可行且可以实现的。这样的成本/效益比 该药物是一种极好的成功候选药物，并且有潜力成为一系列药物中的第一个。 新型药物。我们建议使用合理的设计来识别那些对催化至关重要的氨基酸 活性，然后使用定点诱变，增强人 PON 的天然催化活性 创建一个可行的候选者，以便在五年内过渡到临床试验。这将 解决保护平民免遭恐怖分子袭击的国家目标中的一个关键差距 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。我们将鉴定和开发用于临床测试的人类蛋白质，该蛋白质能够提供快速和 长期持久的预防性保护，防止接触化学战神经毒剂。这样的药物会 实现为广大民众提供更好的保护以免受病毒侵害的重要国家目标 恐怖分子发起的化学武器袭击。