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Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection

Cell-based screening has become the major compound interrogation strategy in Chagas disease drug discovery. Several different cell lines have been deployed as host cells in screening assays. However, host cell characteristics and host-parasite interactions may play an important role when assessing a...

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Autores principales: Franco, Caio Haddad, Alcântara, Laura Maria, Chatelain, Eric, Freitas-Junior, Lucio, Moraes, Carolina Borsoi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630705/
https://www.ncbi.nlm.nih.gov/pubmed/31108888
http://dx.doi.org/10.3390/tropicalmed4020082
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author Franco, Caio Haddad
Alcântara, Laura Maria
Chatelain, Eric
Freitas-Junior, Lucio
Moraes, Carolina Borsoi
author_facet Franco, Caio Haddad
Alcântara, Laura Maria
Chatelain, Eric
Freitas-Junior, Lucio
Moraes, Carolina Borsoi
author_sort Franco, Caio Haddad
collection PubMed
description Cell-based screening has become the major compound interrogation strategy in Chagas disease drug discovery. Several different cell lines have been deployed as host cells in screening assays. However, host cell characteristics and host-parasite interactions may play an important role when assessing anti-T. cruzi compound activity, ultimately impacting on hit discovery. To verify this hypothesis, four distinct mammalian cell lines (U2OS, THP-1, Vero and L6) were used as T. cruzi host cells in High Content Screening assays. Rates of infection varied greatly between different host cells. Susceptibility to benznidazole also varied, depending on the host cell and parasite strain. A library of 1,280 compounds was screened against the four different cell lines infected with T. cruzi, resulting in the selection of a total of 82 distinct compounds as hits. From these, only two hits were common to all four cell lines assays (2.4%) and 51 were exclusively selected from a single assay (62.2%). Infected U2OS cells were the most sensitive assay, as 55 compounds in total were identified as hits; infected THP-1 yielded the lowest hit rates, with only 16 hit compounds. Of the selected hits, compound FPL64176 presented selective anti-T. cruzi activity and could serve as a starting point for the discovery of new anti-chagasic drugs.
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spelling pubmed-66307052019-08-19 Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection Franco, Caio Haddad Alcântara, Laura Maria Chatelain, Eric Freitas-Junior, Lucio Moraes, Carolina Borsoi Trop Med Infect Dis Article Cell-based screening has become the major compound interrogation strategy in Chagas disease drug discovery. Several different cell lines have been deployed as host cells in screening assays. However, host cell characteristics and host-parasite interactions may play an important role when assessing anti-T. cruzi compound activity, ultimately impacting on hit discovery. To verify this hypothesis, four distinct mammalian cell lines (U2OS, THP-1, Vero and L6) were used as T. cruzi host cells in High Content Screening assays. Rates of infection varied greatly between different host cells. Susceptibility to benznidazole also varied, depending on the host cell and parasite strain. A library of 1,280 compounds was screened against the four different cell lines infected with T. cruzi, resulting in the selection of a total of 82 distinct compounds as hits. From these, only two hits were common to all four cell lines assays (2.4%) and 51 were exclusively selected from a single assay (62.2%). Infected U2OS cells were the most sensitive assay, as 55 compounds in total were identified as hits; infected THP-1 yielded the lowest hit rates, with only 16 hit compounds. Of the selected hits, compound FPL64176 presented selective anti-T. cruzi activity and could serve as a starting point for the discovery of new anti-chagasic drugs. MDPI 2019-05-17 /pmc/articles/PMC6630705/ /pubmed/31108888 http://dx.doi.org/10.3390/tropicalmed4020082 Text en © 2019 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
Franco, Caio Haddad
Alcântara, Laura Maria
Chatelain, Eric
Freitas-Junior, Lucio
Moraes, Carolina Borsoi
Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection
title Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection
title_full Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection
title_fullStr Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection
title_full_unstemmed Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection
title_short Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound Selection
title_sort drug discovery for chagas disease: impact of different host cell lines on assay performance and hit compound selection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630705/
https://www.ncbi.nlm.nih.gov/pubmed/31108888
http://dx.doi.org/10.3390/tropicalmed4020082
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