Phosphoinositide-dependent kinase-1 as an antifungal drug target

项目摘要 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（PDK 1）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 对正常细胞，令人遗憾的是，三个PDK 1抑制剂确定在我们的初步工作（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。为了发展 PDK 1/Pkh抑制剂作为抗真菌药物的潜在前景，我们将： 哺乳动物PDK 1抑制剂对真菌PDK 1直系同源物的活性（目的1）;优化抗真菌剂 通过结构-活性分析（目的2）测定两种先导支架（吡唑和羟基吲哚/他汀）的活性;以及 在动物模型中测定新型PDK 1抑制剂的体外和体内功效（目的3）。这种聚焦的 本研究旨在系统评价人PDK 1抑制剂支架的抗真菌活性 并有望导致一流的抗真菌分子的进一步发展。

PROJECT SUMMARY 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 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.