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和一个重组人Buche都在高级发育中 作为Proteting Aginst Aginst化学战剂的潜在预防。这些蛋白质反应迅速， 用sto菌，有效地清除血液中的毒药，但需要相对较大 提供保护的蛋白质量。识别基于蛋白质的药物的挑战 在提供增强用户接受的优势的同时，需要更少的材料，同时提供改进的保护 不能忽略。我们实验室的最新努力已经确定人类二氧酮酶（PON）为蛋白质 可以催化所有神经剂的水解，并且作为自然的血浆酶应该具有 数小时或数天的体内生物利用度。因此，它是哲学给药的出色候选者 为在平民维持和平的急救人员袭击或军事力量的急救人员提供保护 设置构成不对称威胁。如果静脉注射给药，也可以用作快速发作 对暴露于神经毒剂的平民群体的一部分的治疗解毒剂。初步的 研究表明，这些目标都是可行的且可获得的。这样的成本/收益率 药物使它成为成功的绝佳候选者，并且有可能成为一系列A中的第一个 新型药物。我们建议使用理性设计来识别那些对催化性至关重要的氨基酸 活性，然后使用位点直接诱变，增强人PON的天然催化活性 创建一个可行的候选人，以在五年内过渡到临床试验。这会 解决保护平民免受恐怖分子引发的国家目标的关键差距 化学武器攻击。 当前对化学神经毒剂暴露恐怖分子暴露的医疗保护仅限于接触 治疗。我们将确定并开发用于临床测试的人蛋白，能够提供快速和 持久的预防性保护防止暴露于化学战神经剂。这样的药物会 解决了为普通民众提供改进保护的关键国家目标 恐怖分子发起的化学武器攻击。