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Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening

Novel technologies that include recombinant pathogens and rapid detection methods are contributing to the development of drugs for neglected diseases. Recently, the results from the first high throughput screening (HTS) to test compounds for activity against Trypanosoma cruzi trypomastigote infectio...

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Autores principales: Andriani, Grasiella, Chessler, Anne-Danielle C., Courtemanche, Gilles, Burleigh, Barbara A., Rodriguez, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166044/
https://www.ncbi.nlm.nih.gov/pubmed/21912715
http://dx.doi.org/10.1371/journal.pntd.0001298
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author Andriani, Grasiella
Chessler, Anne-Danielle C.
Courtemanche, Gilles
Burleigh, Barbara A.
Rodriguez, Ana
author_facet Andriani, Grasiella
Chessler, Anne-Danielle C.
Courtemanche, Gilles
Burleigh, Barbara A.
Rodriguez, Ana
author_sort Andriani, Grasiella
collection PubMed
description Novel technologies that include recombinant pathogens and rapid detection methods are contributing to the development of drugs for neglected diseases. Recently, the results from the first high throughput screening (HTS) to test compounds for activity against Trypanosoma cruzi trypomastigote infection of host cells were reported. We have selected 23 compounds from the hits of this HTS, which were reported to have high anti-trypanosomal activity and low toxicity to host cells. These compounds were highly purified and their structures confirmed by HPLC/mass spectrometry. The compounds were tested in vitro, where about half of them confirmed the anti-T. cruzi activity reported in the HTS, with IC50 values lower than 5 µM. We have also adapted a rapid assay to test anti-T. cruzi compounds in vivo using mice infected with transgenic T. cruzi expressing luciferase as a model for acute infection. The compounds that were active in vitro were also tested in vivo using this assay, where we found two related compounds with a similar structure and low in vitro IC50 values (0.11 and 0.07 µM) that reduce T. cruzi infection in the mouse model more than 90% after five days of treatment. Our findings evidence the benefits of novel technologies, such as HTS, for the drug discovery pathway of neglected diseases, but also caution about the need to confirm the results in vitro. We also show how rapid methods of in vivo screening based in luciferase-expressing parasites can be very useful to prioritize compounds early in the chain of development.
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spelling pubmed-31660442011-09-12 Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening Andriani, Grasiella Chessler, Anne-Danielle C. Courtemanche, Gilles Burleigh, Barbara A. Rodriguez, Ana PLoS Negl Trop Dis Research Article Novel technologies that include recombinant pathogens and rapid detection methods are contributing to the development of drugs for neglected diseases. Recently, the results from the first high throughput screening (HTS) to test compounds for activity against Trypanosoma cruzi trypomastigote infection of host cells were reported. We have selected 23 compounds from the hits of this HTS, which were reported to have high anti-trypanosomal activity and low toxicity to host cells. These compounds were highly purified and their structures confirmed by HPLC/mass spectrometry. The compounds were tested in vitro, where about half of them confirmed the anti-T. cruzi activity reported in the HTS, with IC50 values lower than 5 µM. We have also adapted a rapid assay to test anti-T. cruzi compounds in vivo using mice infected with transgenic T. cruzi expressing luciferase as a model for acute infection. The compounds that were active in vitro were also tested in vivo using this assay, where we found two related compounds with a similar structure and low in vitro IC50 values (0.11 and 0.07 µM) that reduce T. cruzi infection in the mouse model more than 90% after five days of treatment. Our findings evidence the benefits of novel technologies, such as HTS, for the drug discovery pathway of neglected diseases, but also caution about the need to confirm the results in vitro. We also show how rapid methods of in vivo screening based in luciferase-expressing parasites can be very useful to prioritize compounds early in the chain of development. Public Library of Science 2011-08-30 /pmc/articles/PMC3166044/ /pubmed/21912715 http://dx.doi.org/10.1371/journal.pntd.0001298 Text en Andriani 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
Andriani, Grasiella
Chessler, Anne-Danielle C.
Courtemanche, Gilles
Burleigh, Barbara A.
Rodriguez, Ana
Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening
title Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening
title_full Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening
title_fullStr Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening
title_full_unstemmed Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening
title_short Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening
title_sort activity in vivo of anti-trypanosoma cruzi compounds selected from a high throughput screening
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166044/
https://www.ncbi.nlm.nih.gov/pubmed/21912715
http://dx.doi.org/10.1371/journal.pntd.0001298
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