Thursday, December 26, 2024
12/26/2024
ABSTRACT Trypanosomatid parasites cause some of the most challenging neglected diseases worldwide. The human- pathogenic triumvirate of Trypanosoma brucei spp., Trypanosome cruzi, and Leishmania spp. sickening hundreds of thousands of individuals, causing human African trypanosomiasis, Chagas' disease, and a range of visceral to cutaneous lesions, respectively. However, there are no approved vaccines and treatments are difficult due to side-effects, resistance, and regimens that are unsuitable for resource-limited settings. Therefore, discovery of new drugs is critical for therapy, control, and elimination of these diseases. We have recently shown that the protein kinase, AEK1, which is both highly conserved in these agents yet different from human protein kinases, is essential in the pathogenic bloodstream stage of T. brucei in vitro. We have also chemically validated it as important during infection. To discover T. brucei AEK1 inhibitors we will screen well- curated, focused kinase libraries against the purified enzyme, counterscreening against the closest human paralog, with subsequent testing of compounds on cultured bloodstream stage T. brucei. Such compounds will serve as a starting point for future work to develop drugs for treatment and eradication of human African trypanosomiasis. Surprisingly, few drug targets have been validated across pathogenic trypanosomatid species, despite their closely related proteomes. Therefore, we will test whether AEK1 could serve as a pan- trypanosomatid drug target by determining whether it is essential in the pathogenic stages of Leishmania donovani, and through collaboration, T. cruzi. If so, we will quantify activity of the discovered inhibitors against the L. donovani and T. cruzi enzymes and against L. donovani amastigotes. The results will inform us as to whether AEK1 is a suitable drug target for multiple parasite species, which would leverage future medicinal chemistry aimed at enhancing selectivity, efficacy and bioavailability of compounds identified in this project.
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