Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection
Infection with the protozoan parasite <i>Trypanosoma cruzi</i> causes human Chagas disease. Benznidazole (BNZ) and nifurtimox are the current drugs for the treatment; however, they induce severe adverse side effects in patients; therefore, there is a need to improve the treatment effecti...
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2024-12-01
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| author | Citlali Vázquez Rusely Encalada Isabel Jiménez-Galicia Rogelio Gómez-Escobedo Gildardo Rivera Benjamín Nogueda-Torres Emma Saavedra |
| author_facet | Citlali Vázquez Rusely Encalada Isabel Jiménez-Galicia Rogelio Gómez-Escobedo Gildardo Rivera Benjamín Nogueda-Torres Emma Saavedra |
| author_sort | Citlali Vázquez |
| collection | DOAJ |
| description | Infection with the protozoan parasite <i>Trypanosoma cruzi</i> causes human Chagas disease. Benznidazole (BNZ) and nifurtimox are the current drugs for the treatment; however, they induce severe adverse side effects in patients; therefore, there is a need to improve the treatment effectiveness and efficiency of these drugs for its safer use. <b>Background/Objective</b>: Glyburide, glipizide, and gliquidone, hypoglycemic drugs for diabetes treatment, were previously predicted to bind to dihydrofolate reductase-thymidylate synthase from <i>T. cruzi</i> by in silico docking analysis; they also showed antiproliferative effects against <i>T. cruzi</i> epimastigotes, the stage of the insect vector. In the present study, the potential parasiticidal effect of these antidiabetic drugs was tested in monotherapy and bi-therapy with BNZ in human cells in vitro and in animals. <b>Methods</b>: Evaluation was performed in (a) a model of in vitro infection of <i>T. cruzi</i> trypomastigotes using human fibroblasts as host cells and (b) in mice infected with <i>T. cruzi</i>. <b>Results:</b> The antidiabetic drugs in monotherapy showed antiparasitic effects in preventing infection progression (trypomastigotes release), with an IC<sub>50</sub> of 8.4–14.3 µM in comparison to that of BNZ (0.26 µM) in vitro. However, in bi-therapy, the presence of just 0.5 or 1 µM of the antidiabetics decreased the BNZ IC<sub>50</sub> by 5–10 times to 0.03–0.05 µM. Remarkably, the antidiabetic drugs in monotherapy decreased the infection in mice by 40–60% in a similar extent to BNZ (80%). In addition, the combination of BNZ plus antidiabetics perturbed the antioxidant metabolites in epimastigotes. <b>Conclusions</b>: These results identified antidiabetics as potential drugs in combination therapy with BNZ to treat <i>T. cruzi</i> infection. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-020bcf3cee0745cc98aa755447e25b2a2025-01-24T13:45:01ZengMDPI AGPharmaceuticals1424-82472024-12-011812110.3390/ph18010021Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> InfectionCitlali Vázquez0Rusely Encalada1Isabel Jiménez-Galicia2Rogelio Gómez-Escobedo3Gildardo Rivera4Benjamín Nogueda-Torres5Emma Saavedra6Department of Biochemistry, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, MexicoDepartment of Biochemistry, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, MexicoDepartment of Biochemistry, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, MexicoDepartamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, MexicoLaboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, MexicoDepartamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, MexicoDepartment of Biochemistry, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, MexicoInfection with the protozoan parasite <i>Trypanosoma cruzi</i> causes human Chagas disease. Benznidazole (BNZ) and nifurtimox are the current drugs for the treatment; however, they induce severe adverse side effects in patients; therefore, there is a need to improve the treatment effectiveness and efficiency of these drugs for its safer use. <b>Background/Objective</b>: Glyburide, glipizide, and gliquidone, hypoglycemic drugs for diabetes treatment, were previously predicted to bind to dihydrofolate reductase-thymidylate synthase from <i>T. cruzi</i> by in silico docking analysis; they also showed antiproliferative effects against <i>T. cruzi</i> epimastigotes, the stage of the insect vector. In the present study, the potential parasiticidal effect of these antidiabetic drugs was tested in monotherapy and bi-therapy with BNZ in human cells in vitro and in animals. <b>Methods</b>: Evaluation was performed in (a) a model of in vitro infection of <i>T. cruzi</i> trypomastigotes using human fibroblasts as host cells and (b) in mice infected with <i>T. cruzi</i>. <b>Results:</b> The antidiabetic drugs in monotherapy showed antiparasitic effects in preventing infection progression (trypomastigotes release), with an IC<sub>50</sub> of 8.4–14.3 µM in comparison to that of BNZ (0.26 µM) in vitro. However, in bi-therapy, the presence of just 0.5 or 1 µM of the antidiabetics decreased the BNZ IC<sub>50</sub> by 5–10 times to 0.03–0.05 µM. Remarkably, the antidiabetic drugs in monotherapy decreased the infection in mice by 40–60% in a similar extent to BNZ (80%). In addition, the combination of BNZ plus antidiabetics perturbed the antioxidant metabolites in epimastigotes. <b>Conclusions</b>: These results identified antidiabetics as potential drugs in combination therapy with BNZ to treat <i>T. cruzi</i> infection.https://www.mdpi.com/1424-8247/18/1/21Chagas diseasedrug repurposingantidiabetic drughypoglycemic drugbenznidazolcombination therapy |
| spellingShingle | Citlali Vázquez Rusely Encalada Isabel Jiménez-Galicia Rogelio Gómez-Escobedo Gildardo Rivera Benjamín Nogueda-Torres Emma Saavedra Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection Pharmaceuticals Chagas disease drug repurposing antidiabetic drug hypoglycemic drug benznidazol combination therapy |
| title | Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection |
| title_full | Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection |
| title_fullStr | Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection |
| title_full_unstemmed | Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection |
| title_short | Repurposing the Antidiabetic Drugs Glyburide, Gliquidone, and Glipizide in Combination with Benznidazole for <i>Trypanosoma cruzi</i> Infection |
| title_sort | repurposing the antidiabetic drugs glyburide gliquidone and glipizide in combination with benznidazole for i trypanosoma cruzi i infection |
| topic | Chagas disease drug repurposing antidiabetic drug hypoglycemic drug benznidazol combination therapy |
| url | https://www.mdpi.com/1424-8247/18/1/21 |
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