Phosphoinositide-dependent kinase-1 as an antifungal drug target

磷酸肌醇依赖性激酶 1 作为抗真菌药物靶点

• 批准号: 9607817
• 负责人: Damian J Krysan
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9607817
• 关键词: Phosphoinositide; dependent; kinase; antifungal; drug

Invasive fungal infections are an important cause of morbidity and mortality for people with compromised immunity. Unfortunately, the mortality associated with invasive fungal infections remains unacceptably high. One of the contributing factors to this poor outcome is the fact that there are relatively few therapeutic options for the treatment of invasive fungal infections, particularly when compared to the number of antibiotics available for the treatment of bacterial infections. To identify new antifungal drug candidates, we have initiated a high throughput screening and chemical biology-based project to identify molecules that interfere with fungal cell wall biosynthesis. Application of this strategy has rapidly led to the identification of human phosphoinositide dependent kinase-1 (PDK1) inhibitors as highly active antifungal molecules in vitro. PDK1 inhibitors have been extensively developed as targeted anticancer molecules because of their low toxicity toward normal cells. Encouragingly, two of the PDK1 inhibitors identified in our preliminary work (UCN-01 and OSU-03012) have been, or are being, evaluated in human clinical trials. In order to develop the promising potential of PDK1/Pkh inhibitors as antifungal drugs, we will: characterize the molecular basis for the activity of mammalian PDK1 inhibitors toward fungal PDK1 orthologs (Aim 1); characterize the function of PDK1 orthologs in the human fungal pathogens Candida albicans and Cryptococcus neoformans (Aim 2); determine in vivo efficacy of PDK1 inhibitors in animal models (Aim 3); and optimize antifungal properties of PDK1 inhibitors and identify antifungal PDK1 inhibitors with novel chemical scaffolds (Aim 4). Successful execution of these aims is expected to not only provide a fundamental chemical and biological foundation for the development of antifungal PDK1 molecules but could also lead to the rapid translation of PDK1 inhibitors to clinical use since two of our lead compounds have already been evaluated in human clinical trials.

侵袭性真菌感染是一个重要的原因发病率和死亡率的人妥协 免疫力不幸的是，与侵袭性真菌感染相关的死亡率仍然高得不可接受。 导致这种不良结果的因素之一是治疗选择相对较少 用于治疗侵袭性真菌感染，特别是与抗生素的数量相比， 可用于治疗细菌感染。为了确定新的抗真菌候选药物，我们已经启动了 一个高通量筛选和化学生物学为基础的项目，以确定分子干扰真菌 细胞壁生物合成这一策略的应用迅速导致了人类的识别 磷酸肌醇依赖性激酶-1（PDK1）抑制剂作为体外高活性抗真菌分子。PDK1 由于其低毒性，抑制剂已被广泛开发为靶向抗癌分子 向正常细胞转化令人鼓舞的是，在我们的初步工作中鉴定的两种PDK1抑制剂（UCN-01和 OSU-03012）已经或正在人体临床试验中进行评价。为了发展有前途的 PDK1/PKH抑制剂作为抗真菌药物的潜力，我们将：表征活性的分子基础， 针对真菌PDK1直系同源物的哺乳动物PDK1抑制剂（目的1）;表征PDK1的功能 人类真菌病原体白色念珠菌和新型隐球菌中的直系同源物（目的2）;确定 PDK1抑制剂在动物模型中体内功效（目的3）;以及优化PDK1的抗真菌特性 抑制剂和鉴定具有新型化学支架的抗真菌PDK1抑制剂（Aim 4）。成功执行 这些目标的实现，不仅将为生物学提供基本的化学和生物学基础， 抗真菌PDK1分子的发展，但也可能导致PDK1抑制剂的快速翻译， 临床应用，因为我们的两种先导化合物已经在人体临床试验中进行了评估。