Inhibitors of Anthrax Lethal Factor Metalloproteinase

描述(申请人提供)：炭疽病是由炭疽杆菌引起的感染。炭疽芽孢杆菌孢子在体内沉积后，萌发会导致毒素的表达，包括致命因子，这些毒素是致命的，因为免疫系统的细胞，如巨噬细胞和树突状细胞被破坏。致死因子诱导细胞死亡的机制是由于内源性信号分子丝裂原活化蛋白激酶(MAPKK)的蛋白分解所致。阻止致命因子诱导的MAPKK裂解的化合物将阻止免疫细胞介导的炭疽病死亡。此外，使用炭疽致死因子蛋白酶抑制剂还将阻止生物恐怖分子可以很容易地在具有新的致死潜力的其他生物(例如腺病毒载体)中表达的工程或修饰的致死因子。作为我们第一阶段资助的发现有效的、特定的致命因子活性抑制物在致命因子致死性动物模型中有效性的扩展，我们计划合成具有增强效力、更大的细胞渗透性和对其他具有抗生物恐怖意义的蛋白酶的抑制活性的铅分子类似物，包括肉毒杆菌神经毒素和呋喃--激活保护性抗原的宿主细胞蛋白酶。这项工作将涉及使用X射线结晶学分析、定点突变、动力学酶学和基于细胞的疗效来表征抑制剂的机理和细胞特性。在这项计划中发现的新化合物将在向美国食品和药物管理局提交调查性新药申请之前，在有效性和药代动力学模型中进行评估。这些药物将帮助美国对抗已知的和计划中的对我们安全的威胁。

DESCRIPTION (provided by applicant): Anthrax is the infection caused by the bacterium Bacillus anthracis. Following deposition of Bacillus anthracis spores in the body, germination results in expression of toxins, including lethal factor, that are fatal due to destruction of cells of the immune system such as macrophages and dendritic cells. The mechanism of lethal factor-induced cell death is due to proteolytic cleavage of the endogenous signaling molecule mitogen activated protein kinase kinase (MAPKK). Compounds that block lethal factor-induced cleavage of MAPKK will block immune cell-mediated fatality of anthrax. In addition, use of anthrax lethal factor protease inhibitors will also block engineered or modified lethal factor that bioterrorists could easily express in other organisms (e.g. adenovirus vectors) with new lethal potential. As an extension of our Phase I-funded discovery of potent, specific inhibitors of lethal factor activity with efficacy in an animal model of lethal factor lethality, we plan to synthesize analogues of our lead molecules with enhanced potency, greater cell penetration and inhibitory activity on other proteases of counter bioterrorist interest including botulinum neurotoxins and furin, the host cellular protease that activates protective antigen. This effort will involve mechanistic and cellular characterization of inhibitors using x-ray crystallographic analysis, site-directed mutagenesis, kinetic enzymology and cell-based efficacy. New compounds discovered in this program will be evaluated in models of efficacy and pharmacokinetics prior to submission of an Investigational New Drug application with the US Food and Drug Administration. These drugs will help the United States counter known and planned threats to our safety.