Antidotes to Anthrax Lethal Factor Intoxication

描述（由申请方提供）：炭疽致死因子（LF）是一种在炭疽杆菌感染期间引入哺乳动物宿主细胞的蛋白毒素。LF引起的毒血症是由MAPKK介导的细胞内信号传导途径的破坏导致的，从而导致细胞死亡和免疫抑制。如果不加以控制，细菌的继续生长和毒素的释放会导致败血症、休克，并以宿主死亡而结束。虽然接触这种病原体在性质上是有限的，但炭疽孢子作为生物恐怖主义武器的致命性在2001年通过美国邮件进行的袭击中得到了清楚的证明。需要能够作为LF毒性作用的解毒剂的新疗法来对抗这种真实的威胁。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，遭受显着的缺点。它们的共同点是它们无法保护细胞免受LF的直接影响，在感染后期拯救宿主，以及对“下一代”转基因LF武器的脆弱性。单独直接针对LF活性，或与目前的疗法相结合，将在发生大规模生物恐怖主义炭疽袭击时为普通人群提供最佳保护。PanThera最近的工作已经鉴定出小分子LF抑制剂，其在炭疽致死毒素（LT）的动物模型中提供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。这项UO 1申请中提出的工作将建立在PanThera将LF作为药物靶点的专业知识基础上。通过采用药物化学指导的筛选级联设计，以优化我们目前的铅系列的理化和药代动力学特性，有效的LF抑制剂的ADMET配置文件将被细化，目的是确定口服生物可利用的临床前候选人是安全的，并证明在炭疽致死因子中毒的暴露后动物模型的体内疗效。简短叙述：2001年通过美国邮件进行的袭击清楚地表明了炭疽孢子用作生物恐怖主义武器的致命性。这项研究的目的是确定一种安全有效的药物，能够作为炭疽暴露的毒性作用的解毒剂，以对抗这种持续和真实的威胁。

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.