Challenges in Chagas Disease Drug Development

Abstract

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process.

Keywords: Chagas disease; Trypanosoma cruzi; drug development.

Figure 1

Nitroaromatic drugs used to treat Trypanosoma cruzi infections, or undergoing clinical trial. (A) Reductive metabolism of benznidazole, initiated by TcNTR-1, leads to the production of an unstable hydroxylamine derivative. This is readily converted to a hydroxy intermediate (possibly through a nitrenium ion form), which then reacts with water to generate a dihydro-dihydrooxy. This slowly breaks down to release the highly reactive dialdehyde, glyoxal (circled in red) [24]. The intermediaries and final product can form adducts with proteins, DNA, and small molecules such as glutathione and trypanothione. (B) Nifurtimox is reduced by TcNTR-1, leading to the generation of an unstable hydroxylamine. This decomposes, potentially via a ketoxime intermediate, to form unsaturated (circled in red) and then saturated open-chain nitriles [25]. The unsaturated form mediates trypanocidal activity. (C) Fexinidazole, an NTR-1-activated 5-nitroimidazole prodrug [31], has recently been approved as an oral treatment for African trypanosomiasis [32,33]. It outperforms other nitroaromatic drugs as a curative treatment for experimental T. cruzi infections [34], and is undergoing clinical trial against Chagas disease [35].

Figure 2

Fexinidazole outperforms benznidazole and nifurtimox as a treatment for experimental Trypanosoma cruzi infections. (A) BALB/c mice were infected with bioluminescent T. cruzi CL Brener strain [99]. At the chronic stage of infection (124 days), they were treated with benznidazole (BNZ) or fexinidazole (FXN) (30 mg/kg, orally, once daily) for 5 days (marked by red arrow). Treated mice were immunosuppressed on days 138, 142 and 146 using cyclophosphamide (200 mg/kg, i.p) (red lines). Images were acquired using the Lumina II IVIS system (Caliper Life Science) [100]. (B) BALB/c mice at the acute stage of infection (15 days) were treated with nifurtimox (NFX) or FXN (100 mg/kg, orally, once daily) for 10 days (red arrow), and then immunosuppressed on days 35, 39 and 43 using cyclophosphamide (red line). UT, untreated control mice. Heat-maps are on log10 scales and indicate intensity of bioluminescence from low (blue) to high (red). Full data set available in reference [34].

Figure 3

Monitoring parasite tropism and drug activity in chronic Trypanosoma cruzi infections using ex vivo imaging. (A) BALB/c mice were infected with the bioluminescent T. cruzi CL Brener strain. Animals were sacrificed at various points thereafter, and organs and tissue were removed, arranged in a Petri dish as indicated, and immersed in luciferin [100]. Bioluminescence imaging revealed wide dissemination and high parasite burden at the peak of the acute stage (14 days post-infection), and the effect of immune-mediated control of the infection during the transition to the chronic phase (typically day 40–60). In this infection model, the predominant long-term sites of parasite persistence are the colon and/or stomach. Infection of other organs/tissues is more sporadic, although parasites are often located in the skin [103]. (B) Exploiting ex vivo imaging to assess drug efficacy against chronic T. cruzi infection. Detailed information on parasite tropism and drug susceptibility can be established by including the entire carcass and head of the mouse in the imaging process. In the example shown, benznidazole (BZN) treatment has eliminated detectable parasites. In the nontreated mouse, infection of the head region was observed (parietal, frontal, zygomatic and lacrimal bones; red arrows).