Abstract
Kinetoplastids are the causative agents of leishmaniasis, human African trypanosomiasis, and American trypanosomiasis. They are responsible for high mortality and morbidity in (sub)tropical regions. Adequate treatment options are limited and have several drawbacks, such as toxicity, need for parenteral administration, and occurrence of treatment failure and drug resistance. Therefore, there is an urgency for the development of new drugs. Phenotypic screening already allowed the identification of promising new chemical entities with anti-kinetoplastid activity potential, but knowledge on their mode-of-action (MoA) is lacking due to the generally applied whole-cell based approach. However, identification of the drug target is essential to steer further drug discovery and development. Multiple complementary techniques have indeed been used for MoA elucidation. In this review, the different ‘omics’ approaches employed to define the MoA or mode-of-resistance of current reference drugs and some new anti-kinetoplastid compounds are discussed.
Highlights
Leishmaniasis, Chagas disease, and sleeping sickness are caused by kinetoplastid protozoan parasites and are responsible for high morbidity and mortality rates, especially in developing countries [1,2,3]
It is evident that treatment options should be improved and that new drugs will be needed to sustain adequate disease control
Phenotypic screening has allowed the identification of new or repurposed chemical entities that display promising anti-kinetoplastid activity [14,15,16,17]. This cell-based strategy, does not give adequate insights into the MoA, which is useful for further compound optimization and overall success in drug development [14,18,19]
Summary
Leishmaniasis, Chagas disease, and sleeping sickness are caused by kinetoplastid protozoan parasites and are responsible for high morbidity and mortality rates, especially in developing countries [1,2,3]. Target-based and phenotypic screening are two standard approaches adopted by the pharmaceutical industry to identify novel active chemical entities The former has not been very successful given the lack of fully validated targets and the limited knowledge on their molecular biology [3,4,8]. Selection on axenic stages has the advantage of being simple and relatively fast but lacks biological relevance in T. cruzi and Leishmania as these are intracellular pathogens in the vertebrate host Accepting that this may not be a primary issue in MoA studies, it should be kept in mind that confirmation in the intracellular stage will be needed [61,62]. AMB: Amphotericin B, AP: Allopurinol, BOX: Benzoxaborole, BZN: Benznidazole, IC: Isometamidium chloride, FX: Fexinidazole, GNF: GNF-series, MEL: Melarsoprol, MIL: Miltefosine, NFX: Nifurtimox, NH: Nitroheterocyclics, NIO: Nitro-imidazo-oxazine, OX: Oxaborole PMM: Paromomycin, PTM: Pentamidine, PZP: Pyrazolopyrimidine, Sb: Antimonial, SNF: Sinefungin
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