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，这些毒素由于破坏免疫系统的细胞如巨噬细胞和树突状细胞而致命。致命因子诱导细胞死亡的机制是由于内源性信号分子有丝分裂原激活蛋白激酶（MAPKK）的蛋白水解裂解。阻断致死因子诱导的MAPKK切割的化合物将阻断免疫细胞介导的炭疽死亡。此外，使用炭疽致死因子蛋白酶抑制剂还将阻断生物恐怖分子容易在其他具有新的致死潜力的生物（例如腺病毒载体）中表达的工程或修饰致死因子。作为i期资助的致命因子活性强效特异性抑制剂的延伸，我们计划合成我们的铅分子类似物，具有增强的效力，更大的细胞穿透性和对其他对抗生物恐怖主义的蛋白酶的抑制活性，包括肉毒杆菌神经毒素和furin（激活保护性抗原的宿主细胞蛋白酶）。这项工作将包括利用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来对抑制剂进行机制和细胞表征。在该项目中发现的新化合物将在向美国食品和药物管理局提交新药研究申请之前，在功效和药代动力学模型中进行评估。这些药物将帮助美国应对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.