Principal Investigator (PI)
University of Dundee
The Foundation is providing £328,592 in support.
Chris Elcombe
• Platform experience, in particular for the development of 1536-well screening assays.
• Compounds: access to GSK’s diversity collection and analogues.
• Access to key GSK profiling assays, in particular mammalian cell line screening for toxicity (to identify selective hits).
• In silico profiling: access to GSK’s knowhow to filter hits and select most promising candidates for follow-up.
Cryptococcal meningitis, an invasive fungal disease caused by Cryptococcus neoformans, disproportionally affects people in sub-Saharan Africa, with an estimated annual mortality rate of 180,000 people. While immune-competent people normally remain asymptomatic, immune-compromised patients (usually HIV-related) rapidly develop severe disease, with a high chance of death. The existing treatments were originally developed for other diseases and are not fit-for-purpose in sub-Saharan Africa.
In spite of the urgent need for new drugs, very few concerted drug discovery efforts are on-going. Here we propose to develop and implement an in vitro cell-based screening cascade to enable large-scale cryptococcosis drug discovery. The cascade will consist of a primary high-throughput screening assay and a set of secondary assays to profile compounds against key disease-relevant forms of the fungus.
These assays will be developed starting from well characterised and published protocols. We will use this newly developed cascade to screen a GSK diversity library and identify new potential start points for cryptococcal meningitis drug discovery. The proposed work will provide both the screening platform and chemical matter necessary to boost drug discovery for this highly neglected infectious disease.