Abstract
Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments. In this study, the Davis open access natural product-based library was screened against kinetoplastids (Leishmania donovani DD8, Trypanosoma brucei brucei and Trypanosoma cruzi) using phenotypic assays. The aim of this study was to identify hit compounds, with a focus on improved efficacy, selectivity and potential to target several kinetoplastid parasites. The IC50 values of the natural products were obtained for L. donovani DD8, T. b. brucei and T. cruzi in addition to cytotoxicity against the mammalian cell lines, HEK-293, 3T3 and THP-1 cell lines were determined to ascertain parasite selectivity. Thirty-one compounds were identified with IC50 values of ≤10 µM against the kinetoplastid parasites tested. Lissoclinotoxin E (1) was the only compound identified with activity across all three investigated parasites, exhibiting IC50 values <5 µM. In this study, natural products with the potential to be new chemical starting points for drug discovery efforts for kinetoplastid diseases were identified.
Highlights
Trypanosomatida is a group of kinetoplastid protozoa differentiated into the genus Leishmania and Trypanosoma
In our continuing search for new anti-parasitic compounds from nature, we report here the identification of several bioactive molecules with activity across multiple life cycle stages of three kinetoplastids, L. donovani DD8, T. b. brucei and T. cruzi (Chagas disease: intracellular amastigotes)
Natural products serve as an attractive alternative source of chemical starting points for drug discovery against kinetoplastid parasites [47,48]
Summary
Trypanosomatida is a group of kinetoplastid protozoa differentiated into the genus Leishmania and Trypanosoma. Parasites belonging to the genus Leishmania are the causative agents of leishmaniasis, while Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are the causative agents of human. The other parasite in the genus Trypanosoma is Trypanosoma cruzi, which is responsible for Chagas disease. Around 20 million individuals are infected with kinetoplastid pathogens worldwide leading to 95,000 deaths per year [1]. For Chagas disease and HAT the primary areas of transmission are Latin America and sub-Saharan Africa, respectively [2]. Leishmaniasis is endemic to 98 countries around the globe [3]
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