Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), affects more than six million people worldwide, with its greatest burden in Latin America. Available treatments present frequent toxicity and variable efficacy at the chronic phase of the infection, when the disease is usually diagnosed. Hence, development of new therapeutic strategies is urgent. Repositioning of licensed drugs stands as an attractive fast-track low-cost approach for the identification of safer and more effective chemotherapies. With this purpose we screened 32 licensed drugs for different indications against T. cruzi. We used a primary in vitro assay of Vero cells infection by T. cruzi. Five drugs showed potent activity rates against it (IC50 < 4 µmol L−1), which were also specific (selectivity index > 15) with respect to host cells. T. cruzi inhibitory activity of four of them was confirmed by a secondary anti-parasitic assay based on NIH-3T3 cells. Then, we assessed toxicity to human HepG2 cells and anti-amastigote specific activity of those drugs progressed. Ultimately, atovaquone-proguanil, miltefosine, and verapamil were tested in a mouse model of acute T. cruzi infection. Miltefosine performance in vitro and in vivo encourages further investigating its use against T. cruzi.

Miltefosine and Benznidazole Combination Improve Anti-Trypanosoma cruzi In Vitro and In Vivo Efficacy

“…To date, only three studies have assessed the in vivo efficacy of MLT (Croft et al, 1996;Saraiva et al, 2002;Martinez-Peinado et al, 2021) in mice models of acute infection. While Croft et al observed transient parasitemia suppression without a curative effect or reduction of mortality in mice treated for 5 days at up to 30 mg/kg/day by oral route, Saraiva et al reported parasitic sterilization in all mice treated with 25 mg/kg/day, determined by direct blood observation at 120 dpi and spleen culture for 15 days.…”

“…To date, only three studies have assessed the in vivo efficacy of MLT ( Croft et al., 1996 ; Saraiva et al., 2002 ; Martinez-Peinado et al., 2021 ) in mice models of acute infection. While Croft et al.…”

“…Previous reports indicated that MLT exhibits both in vitro ( Croft et al., 1996 ; Santa-Rita et al., 2000 ) and in vivo activity ( Saraiva et al., 2002 ; Martinez-Peinado et al., 2021 ) against T. cruzi.…”

Identification of compounds with activity against Trypanosoma cruzi within a collection of synthetic nucleoside analogs

“…After 18 h, infected Vero cells were PBS-washed and trypsin-detached, diluted at a concentration of 5×10 5 cells per ml in assay medium and 100 ml of that solution (50000 cells) added to 96-well test plates already containing the compounds. Plates were incubated at 37°C for another 72 h and read with CPRG, as described for the anti-T. cruzi assay (Martinez-Peinado et al, 2021a;Martinez-Peinado et al, 2021b;Martinez-Peinado et al, 2021c).…”

An Updated View of the Trypanosoma cruzi Life Cycle: Intervention Points for an Effective Treatment

“…Many efforts have been made in recent decades to develop new treatments, but the biology of the infection, the complex pathology, and the long-term nature of CD have made it impossible to find new drugs and/or effective treatments. Amlodipine, atenolol, bisoprolol, clioquinol, defibrotide, ivermectin, meglumine, metformin, miltefosine, paromomycin, pentamidine, pyrimethamine, and tinidazole are a few examples of compounds with trypanocidal activity, but the results have been inconclusive in the clinic. , Alternatively, an immune therapy that will control T. cruzi transmission and chronic CD is urgently required. It is widely accepted that a vaccine should include antigens targeting all morphological stages of T. cruzi and should be useful as a prophylactic and therapeutic vaccine.…”