Effect of Proteasome Inhibitors on the African Trypanosome

Effect of Proteasome Inhibitors on the African TrypanosomeHuman African trypanosomiasis (HAT), also known as “sleeping sickness”, is a parasitic disease caused by the protozoan Trypanosoma brucei. The disease can present a variety of symptoms including, fever, headaches, muscle aches, and joint pain. As HAT progresses, it can cause neurological symptoms such as confusion, sleep disturbances, and seizures. If left untreated, HAT can be fatal. Current chemotherapy has serious side-effects and calls for new drugs to be discovered to help manage the disease. In the current study, we aim to repurpose proteasome inhibitors (bortezomib, ixazomib and MG-132) against T. brucei. The overall purpose of this study is to (i) determine the 50% proliferation inhibition concentration of each compound in a GI50 assay, (ii) determine the 50% delayed trypanosomal concentration of compounds in a cidal assay, and (iii) analyze the data to identify the most effective drug against T. brucei. The most active compound will be studied for its molecular effects in T. brucei, focusing on protein degradation pathways. This study will open avenues for “repurposing” an existing drug for possible HAT treatment, thereby abridging the drug discovery pipeline, but can also provide tool compounds for studying important physiological pathways in T. brucei.