A NOVEL TARGET FOR THE DEVELOPMENT OF ANTIFUNGAL AGENTS

抗真菌药物开发的新目标

• 批准号: 6293160
• 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: 2001-02-15 至 2001-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6293160
• 关键词: Aspergillus; Candida albicans; Saccharomyces cerevisiae; Schizosaccharomyces pombe; antifungal agents; biotechnology; chemical registry /resource; chemical structure function; cytoskeletal proteins; cytotoxicity; drug discovery /isolation; drug screening /evaluation; enzyme induction /repression; enzyme inhibitors; high throughput technology; immunocytochemistry; kinesin; liquid chromatography mass spectrometry; molecular genetics; morphometry; mycosis; opportunistic infections

DESCRIPTION (Verbatim from Applicant's Abstract): The increase in opportunistic fungal infections such as candidiasis, zygomycosis, cryptococcosis, histoplasmosis, and Aspergillus and Fusarium infections in immunocompromised individuals, including AIDS patients, the elderly, surgical patients, and burn victims, has demonstrated that these infections are frequently fatal if untreated. In addition, the two accepted therapies, amphotericin B and the azoles, have limited effectiveness and toxic side-effects. There is a clear need for more effective antifungal agents. To address this need, we plan to exploit the opportunity to discover antifungal compounds with a novel mechanism of action by targeting drug discovery efforts on a microtubule motor essential for mitotic progression in Aspergillus. Using a high-throughput screen developed by Cytokinetics, we will isolate inhibitors of this molecule's activity from chemical libraries totaling 230,000 compounds. We will test hits for antifungal activity against a panel of fungi and determine mammalian toxicity using cell-based assays. We have isolated homologs of the Aspergillus target from several pathogens, which we will use in in vitro assays to support our efforts to develop broad-spectrum antifungal compounds. In addition to their anticipated use in treating a number of opportunistic fungal diseases in humans, we expect inhibitors of these targets to have agricultural and animal health applications. PROPOSED COMMERCIAL APPLICATION: There has been a dramatic increase in opportunistic fungal infections in immunocompromised individuals, including AIDS patients, the elderly, transplant patients, and burn victims. The two accepted therapies, amphotericin B and the azoles, have limited effectiveness and toxic side effects. We seek to identify new antifungal agents with a novel mechanism of action. 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（逐字摘自申请人摘要）：机会主义的增加 真菌感染，如念珠菌病、接合菌病、隐球菌病， 免疫功能低下者的组织胞浆菌病、曲霉菌和镰刀菌感染 个人，包括艾滋病患者、老年人、手术患者和烧伤患者 受害者，已经证明这些感染通常是致命的，如果 未经治疗。此外，两种公认的疗法：两性霉素 B 和 唑类药物的疗效有限且有毒副作用。有一个明确的 需要更有效的抗真菌药物。 为了满足这一需求，我们计划利用这个机会发现抗真菌药物 通过靶向药物发现工作，具有新颖作用机制的化合物 对曲霉有丝分裂进展至关重要的微管运动。使用 Cytokinetics 开发的高通量筛选，我们将分离抑制剂 从总共 230,000 种化合物的化学库中了解该分子的活性。 我们将测试针对一组真菌的抗真菌活性， 使用基于细胞的测定确定哺乳动物毒性。我们有分离的同系物 来自几种病原体的曲霉靶标，我们将在体外使用 检测支持我们开发广谱抗真菌化合物的努力。 除了预期用于治疗许多机会性疾病之外 人类真菌疾病，我们预计这些目标的抑制剂 农业和动物健康应用。 拟议的商业应用： 免疫功能低下者的机会性真菌感染急剧增加 个人，包括艾滋病患者、老年人、移植患者和烧伤患者。 这 两种公认的疗法，两性霉素 B 和唑类药物，效果有限，并且 毒副作用。 我们寻求通过新的机制来识别新的抗真菌药物 行动。 目前的抗真菌药物每年的潜在市场销售额为 65 亿美元。 显然，一个 新型广谱抗真菌药物将具有显着的商业价值，并将增加 感染者的生活质量。