Trypanosoma brucei is the causative agent in the disease Human African Trypanosomiasis (HAT), commonly known as African Sleeping Sickness.  In 2009, nearly 10,000 new cases were reported in sub-Saharan Africa. Current treatments for HAT are complicated, difficult to administer, and are beleaguered by problems with toxicity. In addition, drug resistance threatens successful control of the disease. Hence, there is a clear need for novel drugs that are safe, effective, and overcome drug resistance. Our approach to developing new small-molecule therapeutics is to target protein kinases, which are attractive drug targets because they have been shown to play important roles in cell signaling pathways and have proven to be druggable targets in other organismal systems. Recently, we identified a kinase inhibitor that potently inhibits the growth of the bloodstream form of T. brucei. In an effort to find the target(s) of this inhibitor we used two complementary proteomic approaches and identified nearly twenty kinases that bind selectively to the inhibitor. We then used conditional gene knockouts and RNAi experiments to determine that four of the identified kinases are essential for normal parasite growth. These four kinases, primarily from the STE kinase group, are promising targets for small-molecule therapies. Further studies should enable the development of inhibitors that bind selectively to T. brucei  kinases, serving as valuable starting points for HAT therapies  that are not toxic to humans.

Identification of protein kinase targets for the treatment of Human African Trypanosomiasis using chemical proteomic and genetic strategies

247th National Meeting (2014)

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