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High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi

Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, whi...

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Autores principales: Bernatchez, Jean A., Chen, Emily, Hull, Mitchell V., McNamara, Case W., McKerrow, James H., Siqueira-Neto, Jair L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232187/
https://www.ncbi.nlm.nih.gov/pubmed/32224991
http://dx.doi.org/10.3390/microorganisms8040472
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author Bernatchez, Jean A.
Chen, Emily
Hull, Mitchell V.
McNamara, Case W.
McKerrow, James H.
Siqueira-Neto, Jair L.
author_facet Bernatchez, Jean A.
Chen, Emily
Hull, Mitchell V.
McNamara, Case W.
McKerrow, James H.
Siqueira-Neto, Jair L.
author_sort Bernatchez, Jean A.
collection PubMed
description Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified seven compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic.
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spelling pubmed-72321872020-05-22 High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi Bernatchez, Jean A. Chen, Emily Hull, Mitchell V. McNamara, Case W. McKerrow, James H. Siqueira-Neto, Jair L. Microorganisms Article Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection, T. cruzi can cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened 7680 compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a collection of drugs or compounds with confirmed clinical safety, against T. cruzi. We identified seven compounds of interest with potent in vitro activity against the parasite with a therapeutic index of 10 or greater, including the previously unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of new T. cruzi leads that can potentially move quickly to the clinic. MDPI 2020-03-26 /pmc/articles/PMC7232187/ /pubmed/32224991 http://dx.doi.org/10.3390/microorganisms8040472 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bernatchez, Jean A.
Chen, Emily
Hull, Mitchell V.
McNamara, Case W.
McKerrow, James H.
Siqueira-Neto, Jair L.
High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi
title High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi
title_full High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi
title_fullStr High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi
title_full_unstemmed High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi
title_short High-Throughput Screening of the ReFRAME Library Identifies Potential Drug Repurposing Candidates for Trypanosoma cruzi
title_sort high-throughput screening of the reframe library identifies potential drug repurposing candidates for trypanosoma cruzi
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232187/
https://www.ncbi.nlm.nih.gov/pubmed/32224991
http://dx.doi.org/10.3390/microorganisms8040472
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