Direct Inhibition of Antrhax Toxin Action

除了暴露了我们对生物恐怖主义的普遍脆弱性外，2001年秋季的炭疽袭击还提醒了 国家认识到需要开发针对炭疽杆菌的治疗方法和疫苗。炭疽杆菌产生两种 主要毒力因素--抗吞噬多D-谷氨酸胶囊和三方毒素。注射用 这种纯化的毒素能迅速杀死敏感的啮齿动物和非人类灵长类动物，并对 这种毒素可防止感染。因此，人们普遍认为，炭疽感染导致的死亡 从毒素的影响。作为开发炭疽病新的治疗干预措施的一步，我们 建议使用高通量筛选来鉴定低分子质量化合物，这些化合物可以抑制 炭疽毒素在细胞水平。我们已经开发了一种基于这种毒素对人的影响的灵敏分析方法 小鼠巨噬细胞。根据科利尔实验室研究炭疽毒素的经验，我们将 描述发现的最有希望的抑制剂，以确定每种毒素作用的具体步骤 抑制。低毒的先导化合物将被考虑用于毒素作用的动物模型测试。

Besides exposing our general vulnerability to bioterrorism, the anthrax attacks of the fall of 2001 alerted the nation to the need to develop therapies and vaccines against Bacillus anthracis. B. anthracis produces two major virulence factors--an antiphagocytic poly-D-glutamic acid capsule and a tripartite toxin. Injection of the purified toxin causes rapid death of sensitive rodents and non-human primates, and immunization against the toxin protects against infection. Thus it is generally believed that death from anthrax infections results from the effects of the toxin. As a step towards developing new therapeutic interventions for anthrax, we propose to use a high-throughput screen to identify low molecular mass compounds that inhibit the action of anthrax toxin at the cellular level. We have developed a sensitive assay based on the effect of this toxin on mouse macrophages. Building on the experience of the Collier laboratory in studying anthrax toxin, we will characterize the most promising inhibitors found, to determine the specific step in toxin action that each inhibits. Lead compounds with low toxicity will be considered for testing in animal models of toxin action.