Inhibitors of Anthrax Lethal Factor Metalloproteinase

描述（由申请人提供）：炭疽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，萌发导致毒素的表达，包括致命因子，由于免疫系统细胞如巨噬细胞和树突细胞的破坏，这些毒素是致命的。致死因子诱导的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激酶（MAPKK）的蛋白水解裂解。阻断致死因子诱导的MAPKK裂解的化合物将阻断免疫细胞介导的炭疽致死性。此外，炭疽致死因子蛋白酶抑制剂的使用还将阻断生物恐怖分子可以容易地在具有新的致死潜力的其他生物体（例如腺病毒载体）中表达的工程化或修饰的致死因子。作为我们I期资助的发现的延伸，在致死因子致死性的动物模型中有效的致死因子活性的有效的特异性抑制剂，我们计划合成我们的先导分子的类似物，其具有增强的效力，更大的细胞渗透性和对其他生物恐怖分子感兴趣的蛋白酶的抑制活性，包括肉毒杆菌神经毒素和弗林蛋白酶，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射线晶体学分析，定点诱变，动力学酶学和基于细胞的功效的抑制剂的机制和细胞表征。在向美国食品药品监督管理局提交研究性新药申请之前，将在有效性和药代动力学模型中评估本项目中发现的新化合物。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.