Antidotes to Anthrax Lethal Factor Intoxication

炭疽致死因子中毒的解毒剂

• 批准号: 7617669
• 负责人: ALAN THOMAS JOHNSON
• 金额: $ 106.75万
• 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/7617669
• 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（由申请人提供）：炭疽致死因子（LF）是一种蛋白质毒素，该蛋白毒素在细菌炭疽杆菌感染期间引入了哺乳动物宿主的细胞中。由于LF引起的毒血症是由于MAPKK介导的细胞内信号传导途径的破坏导致细胞死亡和免疫抑制。未经检查，细菌的持续生长和毒素的释放导致败血症，冲击，并随着宿主的死亡而结束。尽管这种病原体的暴露在本质上是有限的，但在2001年通过美国邮件袭击中清楚地证明了炭疽孢子的致死性。需要对LF的有毒作用充当解毒剂的新型治疗剂才能应对这种真正的威胁。现有的治疗方法，例如目前正在开发的抗生素，疫苗和生物疗法，都有很大的缺点。每个人的共同点是它们无法保护细胞免受LF的直接影响，在后期感染期间拯救宿主以及“下一代”转基因LF武器的脆弱性。在大规模的生物恐怖主义炭疽病攻击的情况下，直接靶向LF活动，或与当前疗法结合使用，将为普通人群提供最佳保护。 Panthera的最新工作导致了小分子LF抑制剂的鉴定，这些抑制剂可在炭疽致死毒素（LT）的动物模型中提供100％的生存能力。这项早期的概念验证研究清楚地表明，我们当前的铅系列的内在结构可以在体内起作用，作为对LT的解毒剂。在本次UO1应用程序中提出的工作将基于Panthera对LF作为药物目标的专家知识。 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.简短的叙述：在2001年通过美国邮寄的攻击中清楚地证明了炭疽孢子的致命性。这项研究的目的是确定一种安全有效的药物，能够充当对毒性作用的解毒剂，这是由于炭疽病的暴露以应对这种持续和真正的威胁。