Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivo

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Pandey, Ramendra P. ; Nascimento, Marilda Savoia ; Franco, Caio Haddad ; Bortoluci, Karina ; Silva, Marcelo Nunes ; Zingales, Bianca ; Gibaldi, Daniel ; Barrios, Leda Castano ; Lannes-Vieira, Joseli ; Cariste, Leonardo Moro ; Vasconcelos, Jose Ronnie ; Moraes, Carolina Borsoi ; Freitas-Junior, Lucio H. ; Kalil, Jorge ; Alcantara, Laura ; Cunha-Neto, Edecio

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 66, n. 11, p. 17-pg., 2022-10-31.

Resumo

Drug combinations and drug repurposing have emerged as promising strategies to develop novel treatments for infectious diseases, including Chagas disease. In this study, we aimed to investigate whether the repurposed drugs chloroquine (CQ) and colchicine (COL), known to inhibit Trypanosoma cruzi infection in host cells, could boost the anti-T. cruzi effect of the trypanocidal drug benznidazole (BZN), increasing its therapeutic efficacy while reducing the dose needed to eradicate the parasite. The combination of BZN and COL exhibited cytotoxicity to infected cells and low antiparasitic activity. Conversely, a combination of BZN and CQ significantly reduced T. cruzi infection in vitro, with no apparent cytotoxicity. This effect seemed to be consistent across different cell lines and against both the partially BZN-resistant Y and the highly BZN-resistant Colombiana strains. In vivo experiments in an acute murine model showed that the BZN+CQ combination was eight times more effective in reducing T. cruzi infection in the acute phase than BZN monotherapy. In summary, our results demonstrate that the concomitant administration of CQ and BZN potentiates the trypanocidal activity of BZN, leading to a reduction in the dose needed to achieve an effective response. In a translational context, it could represent a higher efficacy of treatment while also mitigating the adverse effects of high doses of BZN. Our study also reinforces the relevance of drug combination and repurposing approaches in the field of Chagas disease drug discovery. (AU)

• Processo FAPESP: 16/15209-0 - Novas terapias para Doença de Chagas: repurposing (reposicionamento) de drogas com efeito na invasão da célula hospedeira pelo T. cruzi, potenciação do efeito do benzonidazol em cepas resistentes e em modelo de cardiopatia chagásica crônica em hamsters
• Beneficiário: Edecio Cunha Neto
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa em Políticas Públicas para o SUS
• Processo FAPESP: 14/50708-2 - Effect of nanoparticles containing a drug combination targeting different steps of the T. cruzi cell invasion/replication on T. cruzi infection
• Beneficiário: Ramendra Pati Pandey
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado