Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

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Abstract

Trypanosomatid parasites can cause life-threatening diseases, such as human African trypanosomiasis, leishmaniasis and Chagas disease. In this Review, Gilbert and colleagues discuss the drug discovery landscape and describe some of the challenges that are involved in the development of new drugs to treat these diseases.

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The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications.

Bianca Zingales, Michael Miles, David A. Campbell … (2012)

The protozoan Trypanosoma cruzi, its mammalian reservoirs, and vectors have existed in nature for millions of years. The human infection, named Chagas disease, is a major public health problem for Latin America. T. cruzi is genetically highly diverse and the understanding of the population structure of this parasite is critical because of the links to transmission cycles and disease. At present, T. cruzi is partitioned into six discrete typing units (DTUs), TcI-TcVI. Here we focus on the current status of taxonomy-related areas such as population structure, phylogeographical and eco-epidemiological features, and the correlation of DTU with natural and experimental infection. We also summarize methods for DTU genotyping, available for widespread use in endemic areas. For the immediate future multilocus sequence typing is likely to be the gold standard for population studies. We conclude that greater advances in our knowledge on pathogenic and epidemiological features of these parasites are expected in the coming decade through the comparative analysis of the genomes from isolates of various DTUs. Copyright © 2012 Elsevier B.V. All rights reserved.

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Spiroindolones, a potent compound class for the treatment of malaria.

Matthias Rottmann, Case McNamara, Bryan K. S. Yeung … (2010)

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.