Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds
Chagas disease is caused by the protozoan parasite <i>Trypanosoma cruzi</i> 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 durin...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/2/688 |
| Summary: | Chagas disease is caused by the protozoan parasite <i>Trypanosoma cruzi</i> 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. <i>T. cruzi</i> 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-<i>T. cruzi</i> 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 (IC<sub>50</sub> = 0.27 μmol L<sup>−1</sup>) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind <i>T. cruzi</i> Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic <i>T. cruzi</i> infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. |
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| ISSN: | 1661-6596 1422-0067 |