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

Abstract

The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.

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Figure 1. The drug discovery process.

Drug discovery progresses through several stages and each stage involves specific steps and regulations. The failure rate at each stage is high, which underscores the need for an active pipeline of drug discovery projects.

Figure 2. Antitrypanosomatid compounds currently in preclinical and clinical development.

a | Several compounds are currently in preclinical and clinical development for human African trypanosomiasis (HAT), visceral leishmaniasis (VL) and Chagas’ disease (CD). b | Antitrypansomatid compounds identified through phenotypic approaches that have been progressed into clinical trials.

Figure 3. Molecular targets in trypanosomatids.

a | trypanosomatids show unique metabolic pathways and cellular functions that are attractive for drug discovery. Many enzymes are divergent from other eukaryotes and they have unique or highly specialized organelles such as the kinetoplast and the glycosome, respectively. b | For some antitrypansomatid compounds the molecular targets are known. DDD85646 targets N-myristoyltransferase (NMT); posaconazole and ravuconazole are CYP51 inhibitors; K777 irreversibly inhibits the cysteine protease cruzipain; and GNF6702 selectively inhibits the trypanosomatid proteasome.

Figure 4. Phenotypic approaches to discover antitrypanosomatid compounds.

Various lifecycle stages can be used for the purpose of hit discovery that range from insect forms to host-stage forms in animal models. The different technologies that can be used for phenotypic assays depend on the parasite form and stage and have specific advantages and disadvantages. Examples of compounds whose antitrypanosomal activity was detected using insect forms, in vitro host-stage forms and animal models are shown.