Biological factors that impinge on Chagas disease drug development

Abstract

SUMMARYChagas disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi, and is the most important parasitic infection in Latin America. The current drugs, benznidazole and nifurtimox, are characterized by limited efficacy and toxic side-effects, and treatment failures are frequently observed. The urgent need for new therapeutic approaches is being met by a combined effort from the academic and commercial sectors, together with major input from not-for-profit drug development consortia. With the disappointing outcomes of recent clinical trials against chronic Chagas disease, it has become clear that an incomplete understanding of parasite biology and disease pathogenesis is impacting negatively on the development of more effective drugs. In addition, technical issues, including difficulties in establishing parasitological cure in both human patients and animal models, have greatly complicated the assessment of drug efficacy. Here, we outline the major questions that need to be addressed and discuss technical innovations that can be exploited to accelerate the drug development pipeline.

Synthesis and Evaluation of Nifurtimox–Adamantane Adducts with Trypanocidal Activity

“…[3] The availabled rugs against these neglected tropical diseases (NTDs) are characterizedb yt oxicity, limited efficacy,a nd increasingr esistance. [4] For example, nifurtimoxa nd benznidazole ( Figure 1), which are used against CD, can cause severe side effects, and treatment is often unsuccessful. [5] This has led the World Health Organization (WHO) to coordinate public sector and private partnerships as part of ag lobale ffort to develop new ands afer dugs.…”

“…These new adamantane derivatives exhibited an interesting pharmacological profile in terms of trypanocidal activity and selectivity.The mostactiveadduct with the best selectivity in this study wasfound to be the phenylacetoxy hydrazone 1b Vector-borne kinetoplastid diseases, such as Chagas disease (CD), [1] leishmaniasis, and human African trypanosomiasis (HAT), [2] threaten almost ab illion people worldwide. [4] For example, nifurtimoxa nd benznidazole (Figure 1), which are used against CD, can cause severe side effects, and treatment is often unsuccessful. [4] For example, nifurtimoxa nd benznidazole (Figure 1), which are used against CD, can cause severe side effects, and treatment is often unsuccessful.…”

Nanoemulsions of sulfonamide carbonic anhydrase inhibitors strongly inhibit the growth of Trypanosoma cruzi

“…3 Concentration in cytotoxic lg ml À1 to 50% of RAW 267.4 cells. 4 IS 50 Selectivity index of 50% ¼ CC 50 /IC 50 . a, b,c,d in the rows, means followed by different letters differ statistically (p < .05).…”

“…Due to these modes of transmission the disease is spreading to nonendemic countries including Australia, Canada, Japan, Spain, and the USA 2,3 . The drugs used for the treatment of the disease are the nitroheterocyclic compounds benznidazole and nifurtimox but both of them induce severe side effects and cross-resistance 4 . New therapeutic approaches and new drugs are investigated constantly, and in the present work, nanoemulsions (NEs) of sulfonamides derivatives with inhibitory effects against the carbonic anhydrase (CA, EC 4.2.1.1) from Trypanosoma cruzi were developed.…”

Non-invasive monitoring of drug action: a new livein vitroassay design for Chagas’ disease drug discovery

“…In particular, the design of T. cruzi in vitro assays had to be revisited to render them more predictive for the situation in vivo . A number of parameters were proposed for optimization: the choice of strains [5, 6], the life-cycle stages [7], the treatment regimens [8], and assay designs that assessed drug cidality. Tremendous progress has been made, especially in the area of high-content imaging technology for phenotypic assays [6, 8-14].…”