WEHI Library – Screening identifies new compounds for HAT
HAT – sleeping sickness | 2008-2009
Eskitis Institute; The Walter and Eliza Hall Institute of Medical Research; University of Melbourne; Swiss Tropical and Public Health Institute
Human African Trypanosomiasis (HAT) is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Current drugs available for the treatment of HAT are difficult to administer and have limited effectiveness across species and at different stages of the disease; there is a considerable need to find alternative and less toxic drugs. A well recognised approach to identify starting points for new drug candidates is high throughput screening (HTS) of large compound library collections. We have screened a library of 87,926 compounds against the related trypanosome subspecies, Trypanosoma brucei brucei BS427. Primary hits identified against T.b. brucei were retested and the IC50 value for each compound was estimated for both T.b. brucei and the mammalian cell line HEK293, to determine a selectivity index for each compound. The screening campaign identified 205 compounds with greater than 10 times selectivity against T.b. brucei. Analysis of these compounds, taking into account the required chemical and drug-like structural properties, gave rise to a panel of eight compounds for further biological analysis. These compounds had IC50 values ranging from 0.22 mM to 4 mM with associated selectivity indices ranging from 19 to greater than 345. Further testing against T.b. rhodesiense led to the selection of 6 compounds from 5 new classes with activity against the causative species of HAT which can be considered potential candidates for HAT early drug discovery.