Administrative Core for Center Management and Operations

中心管理和运营的行政核心

• 批准号: 8551631
• 负责人: Douglas Mark Cerasoli
• 金额: $ 19.76万
• 依托单位: U.S. ARMY MEDICAL RESEARCH INST CHEM DEF
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551631
• 关键词: Address; Adoption; Advanced Development; Agreement; Algae; Antidotes; Arizona; Blood; Blood Circulation; Butyrylcholinesterase; Chemical Agents; Chemical Warfare; Chemical Warfare Agents; Chemical Weapons; Chemicals; Chemistry; China; Cholinesterase Inhibitors; Clinical Trials; Collection; Conflict (Psychology); Costs and Benefits; Enzymes; Ethiopia; Evaluation; Exposure to; General Population; Germany; Goals; Human; Human Activities; Human Resources; Hydrolase; Hydrolysis; In Vitro; Insecticides; Institutes; Institution; International; Iran; Iraq; Israel; Japan; Laboratories; Lead; Medical; Medical Research; Military Personnel; Molecular Evolution; Molecular and Cellular Biology; Nature; Office of Administrative Management; Ohio; Paraoxon; Pesticides; Pharmaceutical Preparations; Plants; Plasma; Poison; Poisoning; Population; Production; Proteins; Recombinants; Research; Research Infrastructure; Research Institute; Research Project Grants; Resources; Sarin; Series; Site; Stream; Synapses; System; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Universities; Vertebrates; Vulnerable Populations; World War II; aryldialkylphosphatase; base; bioscavenger; design; drug discovery; drug production; emergency service responder; improved; in vivo; mutant; nerve agent; novel; operation; programs; prophylactic; research clinical testing; response; success; toxicant; weapons

Two proteins, human plasma BuChE, and a recombinant human BuChE are both in advanced development as potential prophylacitcs for protecting against 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 the laboratories alinged with the Center have identified several human enzymes, paraoxonase (PON) and a mutant of butyrylcholinesterase that can catalyze the hydrolysis of all nerve agents. As such these are excellent candidate for prophylactic administration to provide protection for first responders to a terrorist 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. The center will coordinate the overall effort directed toward the enhancement of the the native catalytic activity of these human enzymes 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.

两种蛋白质，即人血浆Buche和一个重组的人Buche，都在高级发育中，作为预防化学战剂的潜在预防性。这些蛋白质反应迅速和稳定，以有效地清除血液中的毒物，但需要相对较大的蛋白质才能提供保护。识别基于蛋白质的药物的挑战，该药物需要更少的材料，同时提供改进的保护，从而获得增强的用户接受的优势。最近的努力与该中心的实验室确定了几种人类酶，二氧氧酶（PON）和一个可以催化所有神经剂的水解的丁乙酸酯酶突变体。因此，这些是预防施法的绝佳候选者 在平民维持和维持恐怖分子中遭受不对称威胁的恐怖袭击或军事力量的第一响应者。如果是静脉内给予的，它也可以用作暴露于神经药物的平民群中的一部分的快速发作的治疗解毒剂。初步研究表明，这些目标既可行又可获得。这种药物的成本/收益率使得它是成功的极好候选者，并且有可能成为一系列新型药物中的第一家。 该中心将协调这些人类酶的原生催化活性的总体努力，以创建可行的候选者，以在五年内过渡到临床试验。这将解决保护平民免受恐怖分子发起的化学武器袭击的国家目标的一个危险差距。