Chagas Disease Drug Discovery: Toward a New Era

Abstract

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed.

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…To measure antiparasitic activity during acute T. cruzi infection, C57BL/6 mice (Jackson Laboratories) were infected by intraperitoneal (i.p.) injection with 10 6 tissue culture-derived T. cruzi CL trypomastigotes. Treatment was initiated on day 7 postinfection, and five mice per treatment group were dosed p.o.…”

“…Thirty-five days or more after infection, animals were dosed p.o. with various regimens of benznidazole (10,30, and 100 mg/kg q.d.) and posaconazole (10,20,30, and 100 mg/kg q.d.).…”

“…Despite these promising preclinical studies, recent phase 2 clinical trials in patients with intermediate-phase Chagas showed that neither posaconazole nor E1224 (a prodrug of ravuconazole) effected lasting parasitemia suppression, as determined by quantitative PCR, in a majority of patients (10,11). In the same trials, treatment with benznidazole translated into durable clearance of parasitemia/PCR negativity in most patients.…”

Anti-parasitic effect of novel amidines against Trypanosoma cruzi: phenotypic and in silico absorption, distribution, metabolism, excretion and toxicity analysis

“…This result demonstrates that to achieve high anti-T. cruzi activity using the DB766 scaffold a central five membered hetero aromatic ring is required. In addition, is important to take into consideration that a hit compound for CD must be active against both parasite stages and upon the different DTUs in order to be given in the distinct endemic areas of this neglected disease (Chatelain, 2015). …”

Current and Future Chemotherapy for Chagas Disease

“…TPPs are a set of criteria to be followed through the development process and describe the needs and characteristic that the new candidate has to meet in order to constitute an improvement over the current available therapies. Drugs for Neglected Diseases initiative (DNDi), a non-profiting drug research and development organization founded with the objective to develop therapies for neglected diseases, has recently updated a TPP for Chagas disease 39 .…”