Phosphoinositide-dependent kinase-1 as an antifungal drug target

项目总结 侵袭性真菌感染是患者发病和死亡的重要原因 豁免权。不幸的是，与侵袭性真菌感染相关的死亡率仍然高得令人无法接受。 造成这一糟糕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药物候选药物，我们已经启动了 高通量筛选和化学生物学为基础的项目，以确定干扰真菌的分子 细胞壁生物合成。这一策略的应用迅速导致了人类身份的识别 磷脂酰肌醇依赖的激酶-1(PDK1)抑制剂作为高效的体外抗真菌分子。PDK1 由于低毒，抑制剂已被广泛开发为靶向抗癌分子。 对于正常细胞，令人鼓舞的是，我们初步工作中确定的三种PDK1抑制剂(UCN- 01、舒尼替尼和OSU-03012)已经或正在进行人体临床试验。为了发展 PDK1/PKH抑制剂作为抗真菌药物的前景，我们将：表征其分子基础 哺乳动物PDK1抑制剂对真菌PDK1同系物的活性(目标1)；优化抗真菌药物 两种铅支架(吡唑和氧吲哚/司他丁)的结构-活性分析(目标2)； 在动物模型中测定新型PDK1抑制剂的体外和体内疗效(目标3)。这就是焦点 设计研究计划，系统评价人PDK1抑制剂支架的抗真菌活性 并有望为进一步的开发带来一流的抗真菌分子。

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.