Center of Catalytic Bioscanvenger Medical Defense Research II: Discovery, Formula

催化生物扫描仪医疗防御研究中心 II：发现、配方

• 批准号: 8551627
• 负责人: Douglas Mark Cerasoli
• 金额: $ 236.49万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551627
• 关键词: Advanced Development; Atropine; Bioavailable; Biological Availability; Blood; Blood Circulation; Cessation of life; Chlorpyrifos; Convulsants; Development; Diagnosis; Dose; Drug Formulations; Drug Metabolic Detoxication; Ensure; Enzymes; Generations; Goals; Health; Hour; In Vitro; Individual; Intramuscular Injections; Libraries; Life; Medical; Metabolism; Organophosphorus Compounds; Oximes; Paraoxonase 1; Parathion; Pesticides; Pharmaceutical Preparations; Pharmacotherapy; Phorate; Poisoning; Population; Publishing; Recombinants; Reporting; Research; Therapeutic; Treatment Efficacy; United States National Institutes of Health; VX nerve gas; Variant; Vision; Work; base; bioscavenger; conventional therapy; design; directed evolution; drug candidate; enzyme activity; in vivo; meetings; nerve agent; preclinical evaluation; public health relevance; research study; residence; screening; sound; tool

DESCRIPTION (provided by applicant): Organophosphorus (OP) compounds, including both nerve agents and pesticides, represent a serious potential threat to the health of the civilian population. Because they are relatively easy to synthesize, are extremely toxic, and may be difficult to rapidly diagnose or treat in a mass casualty situation, they are considered to be a likely tool for use by terrorists in civilian settings. The CounterACT solicitation identifies a need for a rapid, post-exposure protection that can be easily administered to civilians in a mass casualty scenario. We intent to fulfill this requirement by developing a drug formulation that is amenable to use in an autoinjector, can be delivered via intramuscular injection, will become rapidly bioavailable, will have a sufficient long in vivo residence to protect against slowly metabolized OP compounds, and will have sufficient catalytic efficiency and broad spectrum reactivity to protect against a variety of OP threats. The overarching goal of this U54 Center renewal effort, the "Center for Catalytic Bioscavenger Medical Defense Research II: Discovery, Formulation and Preclinical Evaluation", is to define, characterize, and transition to the NIH for advanced development a drug formulation that will afford post-exposure protection to victims of OP poisoning. The path we will utilize to accomplish this goal has three major initiatives that will be performed in parallel; the vision for this approach is that at the end of year three all of the concurrent efforts will combine to identify a single best candidate drug which will then become the Center's focus for the remaining two years. The first initiative that the Center will pursue is the generation through rationale design, directed evolution, and high throughput library screening of enzyme variants based on OPH (from fi. diminuta) and/or on a recombinant, bacterially expressible paraoxonase 1 (P0N1). Variants will be screened for broad spectrum activity against multiple OP pesticides and nerve agents. They will also be designed to possess high catalytic efficiency, which will allow for the rapid detoxification of OPs in the blood of exposed individuals. These efforts will identify a single "best variant" or cocktail of variants that meet the disparate requirements for high catalytic activity and broad spectrum reactivity. The second major initiative of the Center will be the characterization of different encapsulation and formulation approaches that will stabilize enzyme activity in vitro (to promote economical long term storage), will allow rapid (>5 minutes) bioavailability in circulation after an intramuscular injection (to be consistent with the intended use in a mass casualty situation), and to result in long (>48 hour) circulatory stability, ensuring that protection is afforded against both rapid onset OPs like the G agents, slow onset OPs like VX and VR, and pesticides that require in vivo metabolism to be converted into their more toxic forms; to afford protection against different OP compounds with very disparate distribution profiles, we will require both rapid bioavailability and long-lived circulatory stability. The third major initiative will be a determination of the utility of co- administration of conventional therapeutic drugs (atropine, an oxime, and/or an anti-convulsant) as an adjunct that will enhance the therapeutic efficacy of a catalytic scavenger. One of the only published reports detailing the use of a catalytic bioscavenger to provide protection against an OP also included an experiment where atropine and the oxime 2-PAM were co-administered with an enzyme; the amount of protection afforded was substantially greater than was predicted based on the efficacy of either drug therapy alone, suggesting that the use of conventional therapeutic drugs with a catalytic scavenger may result in a synergistic rather than additive level of protection.

描述（由申请人提供）：有机磷（OP）化合物，包括神经毒剂和杀虫剂，对平民健康构成严重的潜在威胁。由于它们相对容易合成，毒性极大，并且在大规模伤亡情况下可能难以快速诊断或治疗，因此它们被认为是恐怖分子在平民环境中使用的可能工具。 CounterACT 征集确定了对快速、暴露后保护的需求，这种保护可以在大规模伤亡情况下轻松地对平民进行管理。我们打算通过开发一种药物制剂来满足这一要求，该药物制剂适合在自动注射器中使用，可以通过肌肉注射输送，将快速生物利用，将在体内有足够长的停留时间以防止缓慢代谢的OP化合物，并且将具有足够的催化效率和广谱反应活性，可以抵御各种有机磷威胁。 U54 中​​心更新工作的总体目标是“催化生物清除剂医学防御研究中心 II：发现、配方和临床前评估”，是定义​​、表征并向 NIH 过渡以进行高级开发的药物配方，该配方将提供后期开发- OP 中毒受害者的暴露保护。我们实现这一目标的途径包括三个并行实施的主要举措：这种方法的愿景是，在第三年年底，所有同时进行的努力将结合起来确定一种最佳候选药物，该药物将成为该中心剩余两年的重点。该中心将追求的第一个举措是通过原理设计、定向进化和高通量库筛选基于 OPH（来自 fi. diminuta）和/或重组、细菌可表达的对氧磷酶 1 (P0N1) 的酶变体。将对多种 OP 农药和神经毒剂的广谱活性筛选变体。它们还将被设计为具有高催化效率，从而能够快速解毒暴露个体血液中的有机磷农药。这些努力将确定单个“最佳变体”或变体混合物，以满足高催化活性和广谱反应性的不同要求。该中心的第二个主要举措将是不同封装和配制方法的表征，这些方法将稳定体外酶活性（促进经济的长期储存），并在肌肉注射后实现快速（> 5 分钟）循环生物利用度（以与大规模伤亡情况下的预期用途一致），并产生长时间（> 48小时）循环稳定性，确保针对快速起效的OP（如G剂）和缓慢起效的OP（如VX和VR，以及需要在体内代谢转化为毒性更大形式的农药；为了提供针对不同分布情况的不同 OP 化合物的保护，我们需要快速的生物利用度和长寿命的循环稳定性。第三个主要举措是确定常规治疗药物（阿托品、肟和/或抗惊厥药）联合给药作为辅助剂的效用，以增强催化清除剂的治疗功效。唯一发表的一份报告详细介绍了使用催化生物清除剂来提供针对 OP 的保护，其中还包括阿托品和肟 2-PAM 与酶共同施用的实验；所提供的保护量远大于基于单独药物治疗的功效所预测的量，这表明将常规治疗药物与催化清除剂一起使用可能会产生协同作用而不是累加水平的保护。