Project 2: Advancing glyoxylate as a chemical countermeasure

项目 2：推进乙醛酸盐作为化学对策

• 批准号: 10241502
• 负责人: RANDALL T PETERSON
• 金额: $ 37.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241502
• 关键词: Acids; Advanced Development; Antidotes; Automobile Driving; Azides; Binding; Cells; Clinical; Collaborations; Complement; Complex; Consumption; Cyanides; Development; Dose; Drug Kinetics; Electron Transport; Enzymes; Equilibrium; Exposure to; Family suidae; Formulation; Generations; Intramuscular; Intramuscular Injections; Intraperitoneal Injections; Lactate Dehydrogenase; Lead; Mediating; Metabolic; Mitochondria; Modeling; Mus; NADH; Oryctolagus cuniculus; Oxidation-Reduction; Oxygen Consumption; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Property; Proteins; Reaction; Safety; Science; Series; Source; Sulfides; Testing; Toxic effect; Work; Zebrafish; animal efficacy; base; cellular targeting; chemical countermeasure; cytochrome c oxidase; drug development; exposure route; glyoxylate; improved; metabolic phenotype; metabolic poison; novel; product development; synergism

Although several compounds with cyanide antidote activity exist, all function via stoichiometric reaction with free cyanide to form a less-toxic cyanide complex. As such, these cyanide scavengers only work at stoichiometric doses and only prior to cyanide interacting with its target proteins. A cyanide countermeasure that did not rely solely on scavenging of free cyanide would be a highly-valuable addition to the countermeasure arsenal because it could potentially 1) be effective at sub-stoichiometric doses, 2) be used in combination with existing scavenging agents, and 3) provide benefit even after cyanide had bound to its cellular targets. Recent discovery efforts within our consortium have identified glyoxylate as a potent and highly effective cyanide countermeasure. Treatment with glyoxylate rescues zebrafish, mice, and rabbits exposed to cyanide. Remarkably, glyoxylate does not appear to be functioning only as a cyanide scavenger. Rather, it appears to produce a rapid and dramatic metabolic transformation that normalizes several key metabolic derangements induced by cyanide, including perturbations in oxygen consumption, metabolite flux, and redox balance. Thus, glyoxylate appears to function through a mechanism that is very different from existing scavenger-based cyanide countermeasures. As such, it may complement existing countermeasures and provide a completely novel means of reversing cyanide's effects. In this project we will focus on delivering one or more glyoxylate-based countermeasure products. Efforts will include optimization of glyoxylate derivatives for use as cyanide antidotes through standard formulation and optimization strategies. We will also explore LDH, the presumptive glyoxylate target, as a potential source of second-generation cyanide antidotes. Finally, we will test the ability of glyoxylate to rescue the effects of other metabolic poisons, sulfide and azide. Specific aims include: Aim 1. To optimize glyoxylate as a countermeasure for clinical deployment. This aim focuses on formulation of glyoxylate to produce a stable countermeasure product that can be delivered by autoinjector. Aim 2. To develop alternative LDH substrates as second-generation, glyoxylate-like countermeasures. This aim explores a series of alternative LDH substrates as potential cyanide countermeasures through studies in zebrafish, mice, and rabbits. Aim 3. To test glyoxylate as a countermeasure for other metabolic poisons. This aim tests the ability of glyoxylate to reverse the toxic effects of other metabolic poisons including sulfide and azide. Successful completion of this project will deliver at least one fully validated, glyoxylate-based cyanide countermeasure that meets the BARDA requirements for advanced development. It will also fill the pipeline with second-generation countermeasures that exploit metabolic modulation to counteract cyanide toxicity. .

尽管存在几种具有氰化物解毒剂活性的化合物，但所有化合物均通过化学计量反应发挥作用 与游离氰化物形成毒性较小的氰化物络合物。因此，这些氰化物清除剂仅在 化学计量剂量并且仅在氰化物与其靶蛋白相互作用之前。氰化物对策 这不仅仅依赖于清除游离氰化物，这将是对 对抗武器库，因为它可能 1) 在亚化学计量剂量下有效，2) 用于 与现有的清除剂组合，3) 即使在氰化物与其结合后也能提供益处 细胞目标。我们联盟最近的发现工作已确定乙醛酸盐是一种有效且高度 有效的氰化物对策。乙醛酸盐治疗可以拯救暴露于乙醛酸盐的斑马鱼、小鼠和兔子 氰化物。值得注意的是，乙醛酸盐似乎不仅仅充当氰化物清除剂。相反，它 似乎会产生快速而戏剧性的代谢转变，使几个关键的代谢正常化 氰化物引起的紊乱，包括耗氧量、代谢物通量和氧化还原的扰动 平衡。因此，乙醛酸盐似乎通过一种与现有的非常不同的机制发挥作用。 基于清除剂的氰化物对策。因此，它可以补充现有的对策和 提供了一种扭转氰化物影响的全新方法。 在这个项目中，我们将专注于提供一种或多种基于乙醛酸盐的对策产品。 工作将包括通过标准优化用作氰化物解毒剂的乙醛酸盐衍生物 制定和优化策略。我们还将探索 LDH（假定的乙醛酸靶点）作为 第二代氰化物解毒剂的潜在来源。最后我们来测试一下乙醛酸盐的救援能力 其他代谢毒物、硫化物和叠氮化物的影响。具体目标包括： 目标 1. 优化乙醛酸盐作为临床部署的对策。这一目标侧重于 乙醛酸盐的配方，以生产可以通过自动注射器输送的稳定的对抗产品。 目标 2. 开发替代 LDH 底物作为第二代乙醛酸盐类对策。 该目标通过研究探索一系列替代 LDH 底物作为潜在的氰化物对策 在斑马鱼、小鼠和兔子中。 目标 3. 测试乙醛酸盐作为其他代谢毒物的对策。这个目标考验的是能力 乙醛酸盐可逆转其他代谢毒物（包括硫化物和叠氮化物）的毒性作用。 该项目的成功完成将提供至少一种经过充分验证的乙醛酸盐基氰化物 满足 BARDA 高级开发要求的对策。也将填补管道 第二代对策利用代谢调节来抵消氰化物毒性。 。