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Drug Discovery for Chagas Disease: Impact of Different Host Cell Lines on Assay Performance and Hit Compound
Caio Haddad Franco1,2, Laura Maria Alcântara3,4, Eric Chatelain5
1Brazilian Biosciences National Laboratory, National Centre for Research in Energy and Materials, Campinas, SP 13083-970, Brazil. caiohaddadfranco@gmail.com.
Abstract:
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.
Insights
Host cell choice significantly impacts Chagas disease drug discovery screening. Different cell lines yielded vastly different anti-parasitic compound hits, highlighting the need for careful assay selection in anti-trypanosomal research.
Area of Science:
- Parasitology
- Drug Discovery
- Cell Biology
Background:
- Cell-based screening is crucial for identifying new Chagas disease treatments.
- Host cell characteristics and interactions can influence anti-parasitic compound activity.
- Previous studies have not fully explored the impact of different host cell lines on screening outcomes.
Purpose of the Study:
- To evaluate the influence of distinct mammalian host cell lines on high-content screening for anti-trypanosomal compounds.
- To assess how host cell choice affects the identification of potential drug candidates against *Trypanosoma cruzi*.
Main Methods:
- Four mammalian cell lines (U2OS, THP-1, Vero, L6) were used as host cells for *Trypanosoma cruzi* infection.
- High-content screening assays were performed using a library of 1,280 compounds.
- Infection rates and compound susceptibility were analyzed across the different cell lines.
Main Results:
- Infection rates and susceptibility to benznidazole varied significantly among the tested host cell lines.
- Screening identified 82 distinct anti-*T. cruzi* compounds, with only 2 common hits across all cell lines.
- The U2OS cell line assay was the most sensitive, identifying 55 hits, while THP-1 yielded the fewest (16 hits).
- Compound FPL64176 demonstrated selective anti-*T. cruzi* activity.
Conclusions:
- Host cell selection is a critical factor in cell-based screening for Chagas disease drug discovery.
- Assay results, including hit rates and compound identification, are highly dependent on the chosen host cell line.
- Further investigation into host-parasite interactions is warranted, and compound FPL64176 shows promise for future drug development.
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