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

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.