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Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi

An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to addres...

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Autores principales: Planer, Joseph D., Hulverson, Matthew A., Arif, Jennifer A., Ranade, Ranae M., Don, Robert, Buckner, Frederick S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102417/
https://www.ncbi.nlm.nih.gov/pubmed/25033456
http://dx.doi.org/10.1371/journal.pntd.0002977
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author Planer, Joseph D.
Hulverson, Matthew A.
Arif, Jennifer A.
Ranade, Ranae M.
Don, Robert
Buckner, Frederick S.
author_facet Planer, Joseph D.
Hulverson, Matthew A.
Arif, Jennifer A.
Ranade, Ranae M.
Don, Robert
Buckner, Frederick S.
author_sort Planer, Joseph D.
collection PubMed
description An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC(50)'s) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC(50) of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC(50) of 4.4 µM), and an antifolate drug (pyrimethamine, EC(50) of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.
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spelling pubmed-41024172014-07-21 Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi Planer, Joseph D. Hulverson, Matthew A. Arif, Jennifer A. Ranade, Ranae M. Don, Robert Buckner, Frederick S. PLoS Negl Trop Dis Research Article An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC(50)'s) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC(50) of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC(50) of 4.4 µM), and an antifolate drug (pyrimethamine, EC(50) of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease. Public Library of Science 2014-07-17 /pmc/articles/PMC4102417/ /pubmed/25033456 http://dx.doi.org/10.1371/journal.pntd.0002977 Text en © 2014 Planer et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Planer, Joseph D.
Hulverson, Matthew A.
Arif, Jennifer A.
Ranade, Ranae M.
Don, Robert
Buckner, Frederick S.
Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi
title Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi
title_full Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi
title_fullStr Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi
title_full_unstemmed Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi
title_short Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi
title_sort synergy testing of fda-approved drugs identifies potent drug combinations against trypanosoma cruzi
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102417/
https://www.ncbi.nlm.nih.gov/pubmed/25033456
http://dx.doi.org/10.1371/journal.pntd.0002977
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