Exploring Fast And Low-Cost Strategies In Drug Discovery For Chagas Disease: The Alternative Quest For New Effective Treatments

From the south of United States to the south of Argentina there is an endemic illness caused by a parasite named Trypanosoma cruzi. This parasite causes a pathology called Chagas disease (CD), which is a silent condition that affects around seven million people worldwide.

The classical transmission of this parasite involves a Triatomine insect, popularly called the “kissing bug,” that eliminates the parasite in its feces while feeding on a mammalian host, including humans. In contact with the skin, the parasite penetrates the organism and can infect every nucleated cell. Contamination of patients who receive infected organ transplants or infected blood transfusions are other important ways of transmission, as well as from mother to child during pregnancy. These situations require extra concerns from healthcare systems and may be overlooked in non-endemic countries.

Another critical transmission route is through oral ingestion of the parasite in contaminated food, which causes severe complications and fast death. The treatment consists in long oral administration of old drugs called benznidazole (Bz) and nifurtimox, which cause severe side effects and are not effective in the later chronic phase (when most of the patients are diagnosed). Besides, there are many strains of T. cruzi that are naturally resistant to both drugs, and the distribution of these drugs reaches less than one percent of the patients globally.

Scientists have been working effortlessly for many years seeking the “golden pill.” A huge number of new molecules have been designed based on ligand-target interaction through computational molecular modelling; substantial libraries of compounds from the pharmaceutical industry have been made available and tested, going through the hit-to-lead optimization process, but so far, the best ones are still not better than the standard treatment in pre-clinical trials (in vitro and in vivo assays). Additionally, strategies used to find new treatments for other diseases have been assessed in order to provide alternative therapies to patients in shorter time and reduced costs. They consist of repurposing old drugs for the disease and also combining them to the classic etiologic treatment.

Metronidazole (Mtz) is a low-cost antimicrobial agent with broad activity against several pathogens, which is used in the treatment of some infectious diseases, like trichomoniasis and amebiasis. Our study was performed using Mtz under well-established cell culture and animal models. Mtz was first tested upon trypomastigotes and intracellular amastigotes in vitro and even though it presents a lack of activity when given alone, Mtz associated with Bz increased the parasite death rates in vitro. The in vivo assays using mice experimentally infected with T. cruzi and treated with the standard drug (Bz) and Mtz lowered animal mortality. Electrocardiographic exams of the treated mice were performed, and the results demonstrated that the combined treatment using Bz and Mtz protected the heart of the surviving animals against damage caused by the parasitism that was not prevented by using with Bz alone.

These results show that drug repurposing and combined therapy are convenient methodologies that should be encouraged and investigated more in order to decrease budget in research for neglected pathologies like CD, providing effective low-cost choices to patients before we uncover the golden pill.

These findings are described in the article entitled Drug repurposing strategy against Trypanosoma cruzi infection: In vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy, recently published in the journal Biochemical Pharmacology.

This work was conducted by Simões-Silva MR, De Araújo JS, Oliveira GM, Demarque KC, Peres RB, D’Almeida-Melo I, Batista DGJ, Da Silva CF, Cardoso-Santos C, Da Silva PB, Batista MM, and Soeiro MNC from the Fundação Oswaldo Cruz, and Bahia MT from the Universidade Federal de Ouro Preto. This research was conducted in the Laboratório de Biologia Celular do Instituto Oswaldo Cruz Fiocruz in Rio de Janeiro, Brasil. Contact information: [email protected]

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