Development of antifungal agents that target essential protein kinases in A. fumigatus.

烟曲霉是侵袭性曲霉病的主要病原体，这种疾病主要影响免疫功能低下的个体，每年导致20万例危及生命的感染。烟曲霉也在表面上具有免疫能力的人群中引起慢性疾病，影响约300万人，并导致40万人死亡（http://www.gaffi.org/why/fungal-disease-frequency）。大约有2000万人因对烟曲霉的免疫过度活跃而终生患病。目前只有三类药物被推荐用于治疗曲霉病，其中唑类药物被推荐用于主要治疗目的。对唑类药物的耐药性正在迅速出现，感染耐药分离株的个体死亡率几乎为90%。迫切需要开发新的药物来治疗各种形式的曲霉病。我们已经在烟曲霉菌基因组中鉴定了20多种必需的蛋白磷酸酶和蛋白激酶，并使用虚拟筛选管道来评估这些潜在靶点的药物可药性（Thornton等人）。我们的筛选突出了这些蛋白质中一些没有已知功能的配体结合位点。该项目的目的是表征这些功能域，开发筛选分析来监测这些蛋白质的功能，并使用我们的虚拟筛选管道作为起点，识别新的抗真菌药物。

A. fumigatus is the primary etiological agent of invasive aspergillosis, a disease that primarily affects individuals who are immunocompromised, and causes 200k life threatening infections annually. A. fumigatus also causes chronic diseases in the ostensibly immunocompetent population which affects around 3 million individuals and leads to c.400k deaths (http://www.gaffi.org/why/fungal-disease-frequency). About 20 million have lifelong conditions caused by an immune hyperactivity to A. fumigatus. Only three classes of drugs are currently recommended for the treatment of aspergillosis with the azole class being recommended for primary therapeutic purposes. Resistance to the azoles is rapidly emerging and for individuals that are infected with a resistant isolate mortality rates are almost 90%. Development of novel agents to treat all forms of Aspergillosis are desperately needed.We have identified over 20 essential protein phosphatases and protein kinases in the genome of A. fumigatus and have used a virtual screening pipeline to evaluate the druggability of these potential targets (Thornton et al in press). Our screen has highlighted a number of ligand binding sites within these proteins with no known function. The aim of this project is to characterise these functional domains, develop screening assays to monitor the function of these proteins and, using our virtual screening pipeline as a start point, identify novel antifungal agents.