Please use this identifier to cite or link to this item: https://doi.org/10.1002/chem.201200482
Title: Parasite-based screening and proteome profiling reveal orlistat, an FDA-approved drug, as a potential anti Trypanosoma brucei agent
Authors: Yang, P.-Y.
Wang, M.
Liu, K.
Ngai, M.H. 
Sheriff, O.
Lear, M.J. 
Sze, S.K.
He, C.Y. 
Yao, S.Q. 
Keywords: antiparasite agents
drug discovery
orlistat
proteomics
trypanosomiasis
Issue Date: 2-Jul-2012
Citation: Yang, P.-Y., Wang, M., Liu, K., Ngai, M.H., Sheriff, O., Lear, M.J., Sze, S.K., He, C.Y., Yao, S.Q. (2012-07-02). Parasite-based screening and proteome profiling reveal orlistat, an FDA-approved drug, as a potential anti Trypanosoma brucei agent. Chemistry - A European Journal 18 (27) : 8403-8413. ScholarBank@NUS Repository. https://doi.org/10.1002/chem.201200482
Abstract: 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. Go fishing for parasite targets: Orlistat-like small-molecule probes have been tested to show potent trypanocidal activities against Trypanosoma brucei. Subsequent in situ proteomic profiling has identified and validated selected cellular targets (see figure). Given the economic challenges of de novo drug development for neglected diseases, these findings indicate orlistat should be considered further as a new trypanocidal drug. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Source Title: Chemistry - A European Journal
URI: http://scholarbank.nus.edu.sg/handle/10635/76725
ISSN: 09476539
DOI: 10.1002/chem.201200482
Appears in Collections:Staff Publications

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