Trypanosoma brucei is a parasite that causes
African sleeping sickness in humans and
nagana in livestock and is transmitted by the tsetse fly. There is an urgent need for the development of new drugs against
African trypanosomiasis due to the lack of
vaccines and effective drugs.
Orlistat (also called
tetrahydrolipstatin or THL) is an FDA-approved
antiobesity drug targeting primarily the pancreatic and gastric lipases within the gastrointestinal tract. It shows potential activities against
tumors, mycobacteria, and parasites. Herein, we report the synthesis and evaluation of an expanded set of
orlistat-like compounds, some of which showed highly potent trypanocidal activities in both the bloodstream form (BSF) and the procyclic form (PCF) of T. brucei. Subsequent in situ parasite-based
proteome profiling was carried out to elucidate potential cellular targets of the
drug in both forms. Some newly identified targets were further validated by the labeling of recombinantly expressed
enzymes in Escherichia coli lysates. Bioimaging experiments with a selected compound were carried out to study the cellular uptake of the
drug in T. brucei. Results indicated that
orlistat is much more efficiently taken up by the BSF than the PCF of T. brucei and has clear effects on the morphology of mitochondria, glycosomes, and the endoplasmic reticulum in both BSF and PCF cells. These results support specific effects of
orlistat on these organelles and correlate well with our in situ
proteome profiling. Given the economic challenges of de novo
drug development for
neglected diseases, we hope that our findings will stimulate further research towards the conversion of
orlistat-like compounds into new
trypanocidal drugs.