Small Molecule Blockers of B. anthracis Toxin

炭疽芽孢杆菌毒素的小分子阻滞剂

• 批准号: 6895549
• 负责人: VLADIMIR A KARGINOV
• 金额: $ 91.22万
• 依托单位: INNOVATIVE BIOLOGICS, INC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895549
• 关键词: Bacillus anthracis; bacteria infection mechanism; bacterial antigens; bacterial proteins; bacterial toxins; chemical information system; chemical registry /resource; chemical synthesis; combinatorial chemistry; cyclodextrins; cytotoxicity; laboratory mouse; molecular dynamics; small molecule; technology /technique development

DESCRIPTION (provided by investigator): Results from our SBIR Phase I project demonstrated that beta-cyclodextrin derivatives designed to block the trans-membrane channel formed by B. anthracis protective antigen (PA) can inhibit the cytotoxic effects of anthrax toxin at low micromolar concentrations. Based on successful completion of the feasibility study, the overall goal of our Phase II project is to select the best drug candidates for anthrax treatment. To achieve this goal we will perform large-scale design, synthesis and screening of chemical libraries, and test the best candidates in small animal studies. The specific aims of this Phase II study are: (1) Utilize crystallographic coordinates and initial testing data in concert with computational chemistry to design additional beta-cyclodextrin derivatives with increased affinity to the PA pore. (2) Optimize a cell-based assay to screen the inhibition of the anthrax toxin cytotoxic effect, establish and validate cell-based and biochemical assays to test chemical compounds for the ability to block the PA channel. (3) Synthesize representative libraries of beta-cyclodextrin analogues, and screen them using biochemical and cell-based assays. (4) Perform toxicity and efficacy tests in mice using at least five compounds with inhibitory activity at nanomolar concentrations to select drug candidates. Long term goals include subsequent preclinical and clinical studies that will lead to the development of a new anti-anthrax treatment.

描述（由研究者提供）：我们的 SBIR 第一阶段项目的结果表明，旨在阻断炭疽杆菌保护性抗原 (PA) 形成的跨膜通道的 β-环糊精衍生物可以在低微摩尔浓度下抑制炭疽毒素的细胞毒性作用。在成功完成可行性研究的基础上，我们二期项目的总体目标是选择治疗炭疽病的最佳候选药物。为了实现这一目标，我们将进行化学库的大规模设计、合成和筛选，并在小动物研究中测试最佳候选药物。该第二阶段研究的具体目标是：（1）利用晶体坐标和初始测试数据与计算化学相结合，设计出对 PA 孔具有更高亲和力的其他 β-环糊精衍生物。 (2) 优化基于细胞的测定法来筛选炭疽毒素细胞毒作用的抑制作用，建立并验证基于细胞和生化的测定法来测试化合物阻断PA通道的能力。 (3) 合成β-环糊精类似物的代表性文库，并使用生化和基于细胞的测定法对其进行筛选。 (4)使用至少五种纳摩尔浓度的具有抑制活性的化合物在小鼠中进行毒性和功效测试，以选择候选药物。长期目标包括随后的临床前和临床研究，这些研究将导致新的抗炭疽治疗方法的开发。