New therapies for Chagas Disease: repurposing of drugs acting on the invasion of host cells by T. cruzi, and potentiation of benznidazole effect in resistant strains and in the hamster model of chronic chagas disease cardiomyopathy

• Grant number: 16/15209-0
• Support Opportunities: Research Grants - Research in Public Policies for the National Health Care System (PP-SUS)
• Start date: December 01, 2016
• End date: December 31, 2019
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Agreement: CNPq - PPSUS
• Principal Investigator: Edecio Cunha Neto
• Grantee: Edecio Cunha Neto
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Bianca Silvana Zingales ; Edilberto Postól ; Frederico Moraes Ferreira ; Jorge Elias Kalil Filho ; Jose Ronnie Carvalho de Vasconcelos ; Karina Ramalho Bortoluci ; Ludmila Rodrigues Pinto Ferreira Camargo ; Renato Arruda Mortara ; Thales de Brito ; Vera Maria Cury Salemi

Abstract

Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease, with high prevalence (6 million in Latin America) and significant morbimortality, mostly due to heart disorders during the chronic phase of infection. Chagas disease cardiomyopathy has a worse prognosis than cardiomyopathies of different etiologies. In Brazil alone, Chagas disease causes US$ 1.3 bn economical losses/year, and its treatment is an important expense for the Brazilian Universal Healthcare System (SUS). The efficacy of the available drugs, benznidazole and nifurtimox, is low for the chronic phase of Chagas disease, the phase where most patients are diagnosis. The drugs cause frequent side effects that reduce drug compliance, and there are strains resistant to treatment. The rapid deployment of new drug regimens that are effective for chronic phase treatment, low-cost and less toxic than available therapy is a global priority. Repurposing/repositioning of drugs already in clinical use for other diseases is the fastest and cheapest strategy to take new treatments to the clinic. Colchicine and chloroquine are very inexpensive drugs that have been used for decades for the treatment of gouty arthritis, malaria and rheumatic diseases. Colchicine is an inhibitor of microtubule polymerization that interferes with the early steps of invasion of the host cell by T. cruzi. Chloroquine inhibits the acidification of endosomes and reduces the escape of trypanosomes from the parasitophorous vacuole to the cytoplasm. Besides, it can inhibit autophagy, an important process for cellular infection by T. cruzi. Our hypothesis is that the combined treatment using chloroquine and colchicine, that inhibit distinct steps of intracellular infection, with the trypanocidal drug benznidazole, will be more efficacious than benznidazole alone. This may lead to a drastic reduction, and perhaps the erradication of T. cruzi parasitism in cultured mammalian cells in vitro and infected animals. The corollary is that the combined treatment will be more effective in benznidazole-resistant strains of T. cruzi and in the treatment of the chronic phase of infection. In this proposal, we will test the efect of each drug individually or in combination on the in vitro infection of phagocytic and non-phagocytic cells, aiming at obtaining a synergisitic effect between drugs with reduction of benznidazole dose and increased effetiveness as compared to benznidazole alone. This will also be tested in genetically distinct T. cruzi strains (belonging to different DTUs). We will also test these drugs in vivo in an acute T. cruzi infection model with a benznidazole-resistant strain as well as treating chronically T. cruzi infected Syrian hamsters, which is one of the best models of chronic Chagas disease cardiomyopathy. We will also investigate the mechanism of action of the most effective drugs/drug combinations. Preliminary results show synergistic effects of the drug combination in vivo and in vitro, with a reduction of Benznidazole dose necessary to erradicate T. cruzi. We expect to propose a new drug regimen for chronic Chagas disease, ready for a clinical trial in patients. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CHEVILLARD, CHRISTOPHE; NUNES, JOAO PAULO SILVA; FRADE, AMANDA FARAGE; ALMEIDA, RAFAEL RIBEIRO; PANDEY, RAMENDRA PATI; NASCIMENTO, MARILDA SAVOIA; KALIL, JORGE; CUNHA-NETO, EDECIO. Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy. FRONTIERS IN IMMUNOLOGY, v. 9, DEC 3 2018. (16/15209-0, 13/50302-3, 14/50890-5)

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; et al. Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivo. Antimicrobial Agents and Chemotherapy, v. 66, n. 11, p. 17-pg., 2022-10-31. (16/15209-0, 14/50708-2)