Antidotes to Anthrax Lethal Factor Intoxication

炭疽致死因子中毒的解毒剂

• 批准号: 7810734
• 负责人: ALAN THOMAS JOHNSON
• 金额: $ 105.79万
• 依托单位: PANTHERA BIOPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810734
• 关键词: Animal Model; Anthrax Attack; Anthrax disease; Anthrax exposure; Antibiotics; Antidotes; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Bioavailable; Biological Assay; Biological Availability; Biological Response Modifier Therapy; Bioterrorism; Cell Death; Cells; Cessation of life; Characteristics; Chemistry; Development; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; Emergency Situation; Ensure; Event; Exposure to; Funding; General Population; Goals; Growth; Immunosuppression; In Vitro; Infection; Intoxication; Knowledge; Lead; Left; Mails; Mammalian Cell; Mediating; Methods; Mitogen-Activated Protein Kinase Kinases; Nature; Oral; Panthera; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Process; Property; Proteins; Research; Research Personnel; Safety; Screening procedure; Sepsis; Septic Toxemia; Shock; Signal Pathway; Specificity; Staging; Structure; Therapeutic Index; Time; Toxic effect; Toxin; Vaccines; Work; anthrax lethal factor; combat; cost; design; drug discovery; improved; in vitro Assay; in vivo; inhibitor/antagonist; lead series; next generation; novel therapeutics; pathogen; pre-clinical; programs; response; scale up; small molecule; weapons

DESCRIPTION (provided by applicant): Anthrax Lethal Factor (LF) is a protein toxin introduced into the cells of mammalian hosts during infection by the bacterium Bacillus anthracis. The toxemia due to LF results from disruption of intracellular signaling pathways mediated by the MAPKKs resulting in cell death and immunosuppression. Left unchecked, continued growth of the bacteria and release of toxin leads to sepsis, shock, and ends with death of the host. While exposure to this pathogen is limited in nature, the lethality of anthrax spores when used as a bioterrorism weapon was clearly demonstrated in the 2001 attacks through the US mail. Novel therapeutics capable of acting as an antidote to the toxic effects of LF are needed to combat this real threat. Existing treatment methods such as antibiotics, vaccines, and biologic therapies currently in development, suffer from significant drawbacks. Common to each is their inability to protect cells from the direct effects of LF, rescue the host during late-stage infection, and vulnerability to 'next generation' genetically modified LF weapons. Directly targeting LF activity alone, or in combination with current therapies, would provide the best protection for the general population in the event of a large scale bioterrorism anthrax attack. Recent work at PanThera has led to the identification of small molecule LF inhibitors which provide 100% survivability in an animal model of anthrax lethal toxin (LT). This early proof of concept study clearly demonstrates that the intrinsic structure of our current lead series can function in vivo as an antidote to LT. The work proposed in this UO1 application will build on PanThera's expert knowledge of LF as a drug target. By employing medicinal chemistry guided by a screening cascade designed to optimize the physicochemical and pharmacokinetic properties of our current lead series, the ADMET profile of potent LF inhibitors will be refined with the goal of identifying orally bioavailable preclinical candidates that are safe and demonstrate in vivo efficacy in a post-exposure animal model of anthrax lethal factor intoxication. Brief Narrative: The lethality of anthrax spores when used as a bioterrorism weapon was clearly demonstrated in the 2001 attacks through the US mail. The goal of this research is to identify a safe and effective drug capable of acting as an antidote to the toxic effects due to anthrax exposure to combat this continuing and real threat.

描述(申请人提供)：炭疽致死因子(LF)是一种蛋白质毒素，在被炭疽杆菌感染时进入哺乳动物宿主的细胞。由Lf引起的毒血症是由于MAPKKs介导的细胞内信号通路被破坏，导致细胞死亡和免疫抑制。如果不加以控制，细菌的持续生长和毒素的释放会导致败血症、休克，最终导致宿主死亡。虽然对这种病原体的接触在性质上是有限的，但炭疽孢子被用作生物恐怖主义武器时的杀伤力在2001年通过美国邮件发动的袭击中得到了清楚的证明。为了对抗这一真正的威胁，需要能够作为LF毒性影响的解毒剂的新疗法。现有的治疗方法，如抗生素、疫苗和目前正在开发的生物疗法，都存在重大缺陷。它们的共同之处在于，它们无法保护细胞免受LF的直接影响，无法在晚期感染期间拯救宿主，以及对“下一代”转基因LF武器的脆弱性。仅直接针对LF活性，或与目前的治疗方法相结合，将在发生大规模生物恐怖主义炭疽病攻击时为普通民众提供最佳保护。Panthera最近的工作导致了小分子LF抑制剂的鉴定，这种抑制剂在炭疽致命毒素(LT)的动物模型中提供了100%的存活率。这项早期的概念验证研究清楚地表明，我们目前的铅系列的内在结构可以在体内作为LT的解毒剂发挥作用。在这份UO1申请中提出的工作将建立在Panthera作为药物靶标的LF的专业知识的基础上。通过在筛选级联的指导下使用药物化学，以优化我们当前铅系列的物理化学和药代动力学特性，有效的LF抑制剂的ADMET图谱将得到完善，目标是确定口服生物可用的临床前候选药物，这些候选药物是安全的，并在炭疽致死因子中毒的暴露后动物模型中展示体内疗效。简要叙述：炭疽孢子被用作生物恐怖主义武器时的杀伤力在2001年通过美国邮件发动的袭击中得到了清楚的证明。这项研究的目标是确定一种安全有效的药物，能够作为炭疽暴露所致毒性影响的解毒剂，以对抗这一持续和真实的威胁。