Experimental and Clinical Treatment of Chagas Disease: A Review

Abstract

Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.

Figure 1.

Schematic representation of the mode of action of the major drugs with trypanocidal activity. The green boxes represent drugs currently used for treatment, the yellow boxes represent drugs in clinical trials, and the red boxes represent experimental drugs. (A) Bisphosphonates inhibit farnesyl pyrophosphate synthase, which reduces the levels of sterols and other essential poly-isoprenoids compounds, affecting cell viability. (B) Nifurtimox (NFX) and benznidazole (BZ) are reduced by the parasite nitroreductase, resulting in the production of reactive oxygen species (ROS), which directly damage the cells of the parasite. Trypanothione reductase helps relieve the oxidative stress, and inhibitors of this enzyme, such as thioridazine and sulfoximine buthionine (SB), increase the amount of ROS in the intracellular space. (C) The ergosterol biosynthetic pathway is essential for parasite survival. Blocking this pathway leads to loss of cell viability via depletion of essential sterols and accumulation of toxic intermediates. Ergosterol inhibitors and fenarimol analogues target lanosterol C14 demethylase, and amiodarone and dronedarone partially inhibit oxidosqualene cyclase. Phospholipid inhibitors block sterol synthesis, inhibit de novo phospholipid synthesis via Greenberg’s pathway, and inhibit signal transduction enzymes such as phosphatidylinositol phospholipase C. (D) Amiodarone and dronedarone release Ca²⁺ from mitochondria and acidocalcisomes (ACs), which increases Ca²⁺ levels in the cytoplasmic space and compromises cell survival. (E) Cruzipain (CZ) is typically located in the Golgi apparatus, flagellar pocket, and glycosomes and is an essential cysteine protease involved in parasite differentiation, cell invasion, multiplication, and immune evasion. Inhibitors of cruzipain alter the Golgi apparatus, owing to the accumulation of unprocessed cruzipain precursors. This figure appears in color at www.ajtmh.org.