Abstract
Kinetoplastid parasites, including Leishmania and Trypanosoma spp., are life threatening pathogens with a worldwide distribution. Next-generation therapeutics for treatment are needed as current treatments have limitations, such as toxicity and drug resistance. In this study, we examined the activities of established mammalian target of rapamycin (mTOR)/phosphoinositide 3-kinase (PI3K) inhibitors against these tropical diseases. High-throughput screening of a library of 1742 bioactive compounds against intracellular L. donovani was performed, and seven mTOR/PI3K inhibitors were identified. Dose-dilution assays revealed that these inhibitors had half maximal effective concentration (EC50) values ranging from 0.14 to 13.44 μM for L. donovani amastigotes and from 0.00005 to 8.16 μM for T. brucei. The results of a visceral leishmaniasis mouse model indicated that treatment with Torin2, dactolisib, or NVP-BGT226 resulted in reductions of 35%, 53%, and 54%, respectively, in the numbers of liver parasites. In an acute T. brucei mouse model using NVP-BGT226 parasite numbers were reduced to under the limits of detection by five consecutive days of treatment. Multiple sequence and structural alignment results indicated high similarities between mTOR and kinetoplastid TORs; the inhibitors are predicted to bind in a similar manner. Taken together, these results indicated that the TOR pathways of parasites have potential for the discovery of novel targets and new potent inhibitors.
Highlights
Neglected tropical diseases including leishmaniasis, human African trypanosomiasis (HAT, or sleeping sickness), and Chagas disease are caused by the pathogenic protozoans Leishmania spp., Trypanosoma brucei subspecies, and Trypanosoma cruzi, respectively
These findings suggest that mammalian target of rapamycin (mTOR)/phosphoinositide 3-kinase (PI3K) inhibitors have potential applications for treatment of kinetoplastid diseases
We used a high-content screening system to assess a library of 1742 compounds with potential bioactivity against intracellular Leishmania
Summary
Neglected tropical diseases including leishmaniasis, human African trypanosomiasis (HAT, or sleeping sickness), and Chagas disease are caused by the pathogenic protozoans Leishmania spp., Trypanosoma brucei subspecies, and Trypanosoma cruzi, respectively. The drugs used to treat kinetoplastid diseases are often highly toxic, expensive, and limited by administration route These characteristics are significant barriers to their use for treatment of patients in developing countries [14,15,16,17]. More than 35 compounds are being tested in clinical trials for treatment of different types of cancers Many of these compounds have not advanced to late-phase trials due to toxicity and limitations in activity. Khadem et al have demonstrated that selective pharmacological inhibition of the host PI3Kδ with CAL-101 results in significant reductions of parasite burdens in VL and CL animal models [40] These findings suggest that mTOR/PI3K inhibitors have potential applications for treatment of kinetoplastid diseases. Structural modeling of identified inhibitors binding to the TORs of kinetoplastid parasites were predicted to provide insights on the potential mode of inhibition at molecular level
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