In the Search for Novel Treatments for Chagas’ Disease Using Cutting-Edge Imaging Technology
Chagas disease (ChD) is caused by Trypanosoma cruzi (T. cruzi), an intracellular protozoan parasite. ChD has a global mortality of 15,000 annual deaths, and approximately, 8-10 million people are infected. There is growing concern in the United States as autochthonous cases of ChD have been reported in the southern region. The two available treatments are only partially effective and highly toxic. N-aroyl derivatives and α, β-unsaturated ketones have been previously tested against Leishmania, a closely related parasite, demonstrating selective toxicity towards the microorganism. The objective of this study is to evaluate a drug library consisting of 21 α, β-unsaturated ketones and 15 N-aroyl derivatives as anti-trypanosomal treatments. We hypothesized there will be at least one effective candidate from the drug libraries against T. cruzi. High-throughput screening was used to evaluate this. Epimastigote forms of T. cruzi CL Brenner-luc were used to assess the anti-parasitic activity of the compounds through a luciferase viability assay. Six compounds showed low toxicity to Human bone osteosarcoma epithelial cells (U2OS) and Rhesus monkey kidney epithelial cells (LLC-MK2). Six of α, β-unsaturated ketones and three N-aroyl compounds showed good anti-trypanosomal activity with an EC50 ranging from 0.19 nM to 1.00 μM and a selectivity index (SI) ranging from 33 to 526. Our future directions include a) to determine the compounds activity against amastigotes (intracellular form of the parasite) by High-Content Imaging (HCI), b) tested in the murine model of Chagas disease and c) to explore the possible mode of action of the lead(s) compounds.
Amezcua Winter, Karsten Dieter, "In the Search for Novel Treatments for Chagas’ Disease Using Cutting-Edge Imaging Technology" (2021). ETD Collection for University of Texas, El Paso. AAI28720769.