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Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

Barcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, Spain
Department of Pharmacology, Toxicology, and Therapeutics, Veterinary Faculty, Autonomous University of Barcelona, 08193 Bellaterra, Spain
Department of Microbiology, New York University School of Medicine, New York, NY 10010, USA
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 688;
Received: 11 December 2020 / Revised: 28 December 2020 / Accepted: 9 January 2021 / Published: 12 January 2021
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 μmol L−1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. View Full-Text
Keywords: Trypanosoma cruzi; Chagas disease; metabolism drugs; phenotypic assays; cytotoxicity assays; chronic in vivo model; dorsomorphin; 17-DMAG Trypanosoma cruzi; Chagas disease; metabolism drugs; phenotypic assays; cytotoxicity assays; chronic in vivo model; dorsomorphin; 17-DMAG
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MDPI and ACS Style

Martinez-Peinado, N.; Martori, C.; Cortes-Serra, N.; Sherman, J.; Rodriguez, A.; Gascon, J.; Alberola, J.; Pinazo, M.-J.; Rodriguez-Cortes, A.; Alonso-Padilla, J. Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds. Int. J. Mol. Sci. 2021, 22, 688.

AMA Style

Martinez-Peinado N, Martori C, Cortes-Serra N, Sherman J, Rodriguez A, Gascon J, Alberola J, Pinazo M-J, Rodriguez-Cortes A, Alonso-Padilla J. Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds. International Journal of Molecular Sciences. 2021; 22(2):688.

Chicago/Turabian Style

Martinez-Peinado, Nieves, Clara Martori, Nuria Cortes-Serra, Julian Sherman, Ana Rodriguez, Joaquim Gascon, Jordi Alberola, Maria-Jesus Pinazo, Alheli Rodriguez-Cortes, and Julio Alonso-Padilla. 2021. "Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds" International Journal of Molecular Sciences 22, no. 2: 688.

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