Kinases as Druggable Targets in Trypanosomatid Protozoan Parasites

1.1. Kinetoplastid Parasites as Pathogenic Parasites: Overview, Life Cycle, Relevance of Life Stages to Health Over the past decade, neglected tropical diseases (NTDs) have seen a surge in research interest in the area of drug discovery. Protozoan pathogens that cause three of these NTDs, Chagas disease, human African trypanosomiasis (HAT), and leishmaniasis, have been the focus of increasing numbers of reported drug discovery focused publications. This has been fueled by the elucidation of the pathogen genomes, and the ability to map targets between parasite and human enzymes, for which a large amount of target-based drug discovery has been performed, both inside and outside the pharmaceutical industry. It has been aided by the parasites that cause these diseases being cultivatable and amenable to reverse genetic manipulation and by the existence of mouse infection model systems. Their analysis has resulted in important fundamental discoveries, but there remain substantial gaps in knowledge, especially with respect to characteristics that can be the foundation for needed therapeutic interventions. In humans, kinases have been a significant focus of the drug discovery efforts, representing nearly a third of the “druggable genome”,1 and many of these enzymes have been validated with respect to a wide range of therapeutic indications. With this background in mind, this review will focus on tools and approaches for understanding the essentiality of kinase targets in Trypanosoma brucei that causes HAT, T. cruzi that causes Chagas disease, and Leishmania spp. that cause the various types of leishmaniasis, and it will describe recent efforts to translate the understanding of these targets into new therapeutic approaches. While kinases phosphorylate a wide variety of molecules (e.g., lipids, carbohydrates, amino acids, nucleotides, etc.), this review is primarily focused on protein kinases because of their great diversity both in humans and their pathogens. In addition, these kinases play critical biological roles and have been shown to be valid drug targets. We do include in the Chemistry section, however, examples of small molecule discovery efforts that focused on nonprotein kinases. These three parasites belong to the order Kinetoplastidae and cause extensive human suffering and death worldwide, as well as significant economic damage due to diseases that they cause in livestock (Table 1).2 Although they are insect-borne, this review will center upon the human host specific life stages of the parasite because of the relevance to drug discovery. The full life cycles for these three pathogens are reviewed elsewhere in this issue.3 The diseases due to these parasites are quite widespread, but their transmission by insect vectors largely limits their range to tropical and subtropical regions and primarily to poor populations and travelers to the regions with infected vectors. However, transmission also occurs by blood transfusion and ingestion of contaminated foods and infrequently by direct transfer between animals. Table 1 Summary of Epidemiological Characteristics of Chagas Disease, Human African Trypanosomiasis, and Leishmaniasisa