Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1783535329518551040 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7232187 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bernatchezjeana highthroughputscreeningofthereframelibraryidentifiespotentialdrugrepurposingcandidatesfortrypanosomacruzi AT chenemily highthroughputscreeningofthereframelibraryidentifiespotentialdrugrepurposingcandidatesfortrypanosomacruzi AT hullmitchellv highthroughputscreeningofthereframelibraryidentifiespotentialdrugrepurposingcandidatesfortrypanosomacruzi AT mcnamaracasew highthroughputscreeningofthereframelibraryidentifiespotentialdrugrepurposingcandidatesfortrypanosomacruzi AT mckerrowjamesh highthroughputscreeningofthereframelibraryidentifiespotentialdrugrepurposingcandidatesfortrypanosomacruzi AT siqueiranetojairl highthroughputscreeningofthereframelibraryidentifiespotentialdrugrepurposingcandidatesfortrypanosomacruzi |