| Author | Portella, Diogo Crispim Nascimento | |
| Author | Rossi, Erik Aranha | |
| Author | Paredes, Bruno Diaz | |
| Author | Bastos, Tanira Matutino | |
| Author | Meira, Cássio Santana | |
| Author | Nonaka, Carolina Vasques Kymie | |
| Author | Silva, Daniela Nascimento | |
| Author | Caria, Alex Improta | |
| Author | Moreira, Diogo Rodrigo Magalhaes | |
| Author | Leite, Ana Cristina Lima | |
| Author | Oliveira Filho, Gevanio Bezerra de | |
| Author | Barbosa Filho, José Maria | |
| Author | Santos, Ricardo Ribeiro dos | |
| Author | Soares, Milena Botelho Pereira | |
| Author | Souza, Bruno Solano de Freita | |
| Access date | 2021-09-22T17:38:41Z | |
| Available date | 2021-09-22T17:38:41Z | |
| Document date | 2021 | |
| Citation | PORTELLA, Diogo Crispim Nascimento et al. A Novel High-Content Screening-Based Method for Anti- Trypanosoma cruzi Drug Discovery Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Stem Cells International, 2021. | pt_BR |
| ISSN | 1687-966X | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/49134 | |
| Sponsorship | CNPq, FAPESB,
and FINEP. | pt_BR |
| Language | eng | pt_BR |
| Publisher | Hindawi | pt_BR |
| Rights | open access | pt_BR |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Insuficiência Cardíaca | pt_BR |
| Subject in Portuguese | Cardiotoxicidade | pt_BR |
| Subject in Portuguese | Células-Tronco Pluripotentes Induzidas | pt_BR |
| Title | A Novel High-Content Screening-Based Method for Anti- Trypanosoma cruzi Drug Discovery Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1155/2021/2642807 | |
| Abstract | Chagas disease is caused by Trypanosoma cruzi infection and remains a relevant cause of chronic heart failure in Latin America.
The pharmacological arsenal for Chagas disease is limited, and the available anti-T. cruzi drugs are not effective when
administered during the chronic phase. Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have
the potential to accelerate the process of drug discovery for Chagas disease, through predictive preclinical assays in target
human cells. Here, we aimed to establish a novel high-content screening- (HCS-) based method using hiPSC-CMs to
simultaneously evaluate anti-T. cruzi activity and cardiotoxicity of chemical compounds. To provide proof-of-concept data, the
reference drug benznidazole and three compounds with known anti-T. cruzi activity (a betulinic acid derivative named BA5 and
two thiazolidinone compounds named GT5A and GT5B) were evaluated in the assay. hiPSC-CMs were infected with T. cruzi
and incubated for 48 h with serial dilutions of the compounds for determination of EC50 and CC50 values. Automated
multiparametric analyses were performed using an automated high-content imaging system. Sublethal toxicity measurements
were evaluated through morphological measurements related to the integrity of the cytoskeleton by phalloidin staining, nuclear
score by Hoechst 33342 staining, mitochondria score following MitoTracker staining, and quantification of NT-pro-BNP, a
peptide released upon mechanical myocardial stress. The compounds showed EC50 values for anti-T. cruzi activity similar to
those previously described for other cell types, and GT5B showed a pronounced trypanocidal activity in hiPSC-CMs. Sublethal
changes in cytoskeletal and nucleus scores correlated with NT-pro-BNP levels in the culture supernatant. Mitochondrial score
changes were associated with increased cytotoxicity. The assay was feasible and allowed rapid assessment of anti-T. cruzi action
of the compounds, in addition to cardiotoxicity parameters. The utilization of hiPSC-CMs in the drug development workflow
for Chagas disease may help in the identification of novel compounds | pt_BR |
| Affilliation | "Múltipla ver em Notas" | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Chagas' disease | pt_BR |
| Subject | Cardiac insufficiency | pt_BR |
| Subject | Cardiotoxicity | pt_BR |
| Subject | Induced Pluripotent Stem Cells | pt_BR |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
