Phosphoinositide-dependent kinase-1 as an antifungal drug target

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。 朝向正常细胞。令人鼓舞的是，我们初步工作中确定的两种PDK1抑制剂(UCN-01和UCN-01 OSU-03012)已经或正在进行人体临床试验。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：表征其活性的分子基础 针对真菌PDK1同源基因的哺乳动物PDK1抑制剂(目标1)；表征PDK1的功能 人类真菌病原体白色念珠菌和新生隐球菌中的同源物(目标2)；测定 PDK1抑制剂在动物模型中的体内疗效(目标3)；并优化PDK1的抗真菌特性 使用新型化学支架开发和鉴定抗真菌PDK1抑制剂(目标4)。成功执行 这些目标中的一部分预计不仅将为 开发抗真菌PDK1分子，但也可能导致PDK1抑制剂快速转化为 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。

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.