Phosphoinositide-dependent kinase-1 as an antifungal drug target

描述（由申请人提供）：侵袭性真菌感染是免疫力低下人群发病和死亡的重要原因。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，治疗侵袭性真菌感染的治疗选择相对较少，特别是与可用于治疗细菌感染的抗生素数量相比。为了识别新的抗真菌药物候选者，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，以确定干扰真菌细胞壁生物合成的分子。这一策略的应用已迅速导致人磷酸肌醇依赖性激酶-1（PDK 1）抑制剂在体外被鉴定为高活性的抗真菌分子。PDK 1抑制剂已被广泛开发为靶向抗癌分子，因为它们对正常细胞的毒性低，值得注意的是，在我们的初步工作中鉴定的三种PDK 1抑制剂（UCN- 01，舒尼替尼和OSU-03012）已经或正在人体临床试验中进行评估。为了开发PDK 1/Pkh抑制剂作为抗真菌药物的潜力，我们将：表征哺乳动物PDK 1抑制剂对真菌PDK 1直系同源物的活性的分子基础（Aim 1）;通过以下方法优化两种先导支架（吡唑和羟吲哚/istatin）的抗真菌活性： 结构-活性分析（目的2）;以及确定新型PDK 1抑制剂在动物模型中的体外和体内功效（目的3）。这项集中的研究计划旨在系统地评估人类PDK 1抑制剂支架的抗真菌活性，并有望为进一步开发带来一流的抗真菌分子。 公共卫生相关性：侵袭性真菌感染是免疫力低下人群发病和死亡的重要原因。不幸的是，与侵袭性真菌感染相关的死亡率在目前的抗真菌治疗中仍然高得不可接受。本申请中描述的项目专注于开发基于抑制蛋白激酶（PDK 1）的新型低毒性抗真菌药物，该蛋白激酶对酵母存活至关重要，但对成熟的人类细胞并非必不可少。

DESCRIPTION (provided by applicant): 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 rapidy 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 and, encouragingly, three of the PDK1 inhibitors identified in our preliminary work (UCN- 01, sunitinib 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); optimize the antifungal activity of two lead scaffolds (pyrazole and oxyindole/istatin) by structure-activity analysis (Aim 2); and determine the in vitro and in vivo efficacy of the novel PDK1 inhibitors in animal models (Aim 3). This focused research plan is designed to systematically evaluate the antifungal activity of human PDK1 inhibitor scaffolds and will hopefully lead to first-in-class antifungal molecules for additional development. PUBLIC HEALTH RELEVANCE: 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 with current antifungal therapies. The project described in this application is focused on developing new, low toxicity antifungal drugs based on inhibiting a protein kinase (PDK1) that is essential for yeast survival but is not essential for mature human cells.