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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/2/688 |
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| author | Nieves Martinez-Peinado Clara Martori Nuria Cortes-Serra Julian Sherman Ana Rodriguez Joaquim Gascon Jordi Alberola Maria-Jesus Pinazo Alheli Rodriguez-Cortes Julio Alonso-Padilla |
| author_facet | Nieves Martinez-Peinado Clara Martori Nuria Cortes-Serra Julian Sherman Ana Rodriguez Joaquim Gascon Jordi Alberola Maria-Jesus Pinazo Alheli Rodriguez-Cortes Julio Alonso-Padilla |
| author_sort | Nieves Martinez-Peinado |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:01:58Z |
| format | Article |
| id | doaj.art-57d9963b147a4ead9c534019ae5d6a8c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:01:58Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-57d9963b147a4ead9c534019ae5d6a8c2023-12-03T12:58:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122268810.3390/ijms22020688Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier CompoundsNieves Martinez-Peinado0Clara Martori1Nuria Cortes-Serra2Julian Sherman3Ana Rodriguez4Joaquim Gascon5Jordi Alberola6Maria-Jesus Pinazo7Alheli Rodriguez-Cortes8Julio Alonso-Padilla9Barcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, SpainDepartment of Pharmacology, Toxicology, and Therapeutics, Veterinary Faculty, Autonomous University of Barcelona, 08193 Bellaterra, SpainBarcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, SpainDepartment of Microbiology, New York University School of Medicine, New York, NY 10010, USADepartment of Microbiology, New York University School of Medicine, New York, NY 10010, USABarcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, SpainDepartment of Pharmacology, Toxicology, and Therapeutics, Veterinary Faculty, Autonomous University of Barcelona, 08193 Bellaterra, SpainBarcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, SpainDepartment of Pharmacology, Toxicology, and Therapeutics, Veterinary Faculty, Autonomous University of Barcelona, 08193 Bellaterra, SpainBarcelona Institute for Global Health (ISGlobal), Hospital Clínic—University of Barcelona, 08036 Barcelona, SpainChagas 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.https://www.mdpi.com/1422-0067/22/2/688<i>Trypanosoma cruzi</i>Chagas diseasemetabolism drugsphenotypic assayscytotoxicity assayschronic in vivo model |
| spellingShingle | Nieves Martinez-Peinado Clara Martori Nuria Cortes-Serra Julian Sherman Ana Rodriguez Joaquim Gascon Jordi Alberola Maria-Jesus Pinazo Alheli Rodriguez-Cortes Julio Alonso-Padilla Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds International Journal of Molecular Sciences <i>Trypanosoma cruzi</i> Chagas disease metabolism drugs phenotypic assays cytotoxicity assays chronic in vivo model |
| title | Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds |
| title_full | Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds |
| title_fullStr | Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds |
| title_full_unstemmed | Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds |
| title_short | Anti-<i>Trypanosoma cruzi</i> Activity of Metabolism Modifier Compounds |
| title_sort | anti i trypanosoma cruzi i activity of metabolism modifier compounds |
| topic | <i>Trypanosoma cruzi</i> Chagas disease metabolism drugs phenotypic assays cytotoxicity assays chronic in vivo model |
| url | https://www.mdpi.com/1422-0067/22/2/688 |
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