Actin-binding proteins as novel antifungal targets

肌动蛋白结合蛋白作为新的抗真菌靶点

• 批准号: 6337193
• 负责人: Corey Evan Nislow
• 金额: $ 10万
• 依托单位: CYTOKINETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2001-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337193
• 关键词: Aspergillus; Candida; Saccharomyces; Schizosaccharomyces pombe; actin binding protein; antifungal agents; chemical registry /resource; chemical structure function; drug discovery /isolation; drug screening /evaluation; high throughput technology; opportunistic infections

DESCRIPTION (provided by applicant): The increase in opportunistic fungal infections such as candidiasis, zygomycosis, cryptococcosis, histoplasmosis, and Aspergillus and Fusarium infections in immunocompromised individuals, including AJDS patients, the elderly, surgical patients. and burn victims, has demonstrated that these infections are often fatal even with present day therapies. The two accepted therapies, amphotericin B and the azoies, have limited effectiveness and toxic side-effects. Hence, there is a clear need for more effective antifungal agents. To address this need, we plan to discover antifungal therapeutics with novel mechanisms of action by targeting drug discovery efforts on a group of actin-binding proteins essential for cell and membrane integrity in pathogenic fungi. Using a high-throughput screen developed by Cytokinetics, we will isolate inhibitors of these molecules' activities from chemical libraries totaling 225,000 compounds. We will test hits for activity against a panel of fungi and determine mammalian toxicity. In an effort to develop broad-spectrum antifungal compounds, we will use in our high-throughput screen homologs of these targets that we have isolated from multiple fungal pathogens. PROPOSED COMMERCIAL APPLICATION: The increase in patients suffering from opportunistic fungal infections, including AIDS patients, the elderly, transplant patients, and burn victims, has demonstrated these infections are frequently fatal if untreated. The accepted therapies have limited effectiveness and toxic side effects. There is a compelling need to find a new molecular targets and inhibitors of these targets. Current antifungals have potential market sales of $6.5 billion annually. Clearly, a novel, broad-spectrum antifungal will have significant commercial value, and will increase the quality of life for infected individuals.

描述（由申请人提供）：机会性真菌的增加 感染，例如念珠菌病、接合菌病、隐球菌病、组织胞浆菌病、 以及免疫功能低下个体的曲霉菌和镰刀菌感染， 包括AJDS患者、老年人、手术患者。和烧伤受害者， 事实证明，即使在当今，这些感染通常也是致命的 疗法。两种公认的疗法，两性霉素 B 和 azoies，已 效果有限且毒副作用大。因此，显然需要 更有效的抗真菌药物。 为了满足这一需求，我们计划发现新的抗真菌疗法 通过针对一组药物发现工作的行动机制 肌动蛋白结合蛋白对于致病性细胞和膜的完整性至关重要 真菌。使用 Cytokinetics 开发的高通量筛选，我们将 从化学库中分离这些分子活性的抑制剂 总计 225,000 种化合物。我们将针对一组测试活动的命中率 真菌并确定哺乳动物的毒性。致力于开发广谱 抗真菌化合物，我们将在高通量筛选中使用 我们从多种真菌病原体中分离出这些靶标。 拟议的商业应用： 机会性真菌感染患者（包括艾滋病患者）的增加， 老年人、移植患者和烧伤患者已经证明这些感染是 如果不及时治疗，通常会致命。 公认的疗法效果有限且有毒 副作用。 迫切需要寻找新的分子靶点和抑制剂 这些目标。 目前的抗真菌药物每年的潜在市场销售额为 65 亿美元。 清楚地， 一种新型的广谱抗真菌药物将具有重大的商业价值，并将增加 感染者的生活质量。