Chagas Disease Treatment: From New Therapeutic Targets to Drug Discovery and Repositioning

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, currently affects millions of people worldwide although it is only endemic in America. Chagas is considered a neglected tropical disease because it afflicts the low-income and poorest populations in developing regions of the Americas, particularly in remote, rural areas where infrastructure such as adequate housing, sanitation and clinical resources are limited. In addition, governments pay scarce or no attention to this health problem. Benznidazole and nifurtimox, both discovered more than 50 years ago, are the only two drugs available to treat Chagas disease and not only present severe side effects but also are ineffective in the chronic phase of the disease when most of the patients are diagnosed. Recent efforts to develop new treatments for Chagas disease, including posaconazole repositioning and the prodrug of ravuconazole (E1224) trial, have been unsuccessful and remark the urgent need to develop new therapeutic alternatives. The scientific effort must be focused in finding simple, safe and effective drugs that directly target the parasite without harming the patients.

Zoledronate repositioning as a potential trypanocidal drug. Trypanosoma cruzi HPRT an alternative target to be considered

“…Many efforts to identify new targets for Chagas disease are constantly pursued, as recently reviewed [23,24]. However, since nifurtimox and BZN were discovered no other drug was introduced into the market and they are efficient only in the acute phase [1].…”

Benznidazole and amiodarone combined treatment attenuates cytoskeletal damage in Trypanosoma cruzi-infected cardiac cells

“…Current etiological treatment for CD is limited to two nitro compounds, benznidazole (Bz) and nifurtimox (Nif), and both present relevant limitations including the occurrence of resistant strains, the lack of efficacy in the later chronic phase, with low cure rates (8 - 30%) and side effects as: weight loss, nausea, headache and allergic dermatitis ( Bern, 2011 ; Ribeiro et al., 2020 ). Different therapeutic approaches are being used to identify more effective and safer treatment schemes, mostly using drug repurposing and combination strategies ( Miranda and Sayé, 2019 ). Drug combination allows the reduction of doses, costs and time of treatment.…”

Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi

“…Both are far from ideal, with the occurrence of naturally resistant strains, lack of efficacy in the later chronic phase, and severe side effects that led to 10-30% therapy withdrawals (Molina et al, 2015). These limitations highlight an urgent need for novel, potent, and safer drugs for CD, and many strategies have been followed, including drug repurposing and drug combinations (Coura, 2009;Miranda and Saye, 2019).…”