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Mitochondria and Trypanosomatids: Targets and Drugs

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ABSTRACT

The family Trypanosomatidae, flagellated parasitic protozoa, is responsible for important infectious diseases in humans: sleeping sickness, Chagas diseases and leishmaniasis. Currently, development of effective vaccines against these parasites remains an unrealized goal, and clinical management is based on chemotherapeutics. Cost, toxicity and resistance problems of conventional drugs result in an urgent need to identify and develop new therapeutic alternatives. The sound understanding of parasites, biology is key for identifying novel lead structures and new drug targets. This article reviews current knowledge about mitochondrial drug targets and existing drugs against Trypanosoma and Leishmania. In the past, several targets in trypanosomatid mitochondria (electron transport chain, kDNA and topoisomerases, tRNA import and fatty acid synthesis) have been identified. It has been suggested that inhibition of certain targets is involved in triggering apoptosis by impairment of mitochondrial membrane potential and/or production of reactive oxygen species. The inhibitory mechanism of approved drugs, such as pentamidine, nifurtimox, artemisinin and atovaquone, is described in parallel with others products from preclinical studies. In spite of the large amount of genetic information, the analysis of the phenotype of the trypanosomatid mitochondrion in different life stages will remain a useful tool to design new active compounds with selective toxicity against these parasites.

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Abbreviations

DIM:

3,3′diindolylmethane

ETC:

electron transport chain

FAS:

fatty acid synthesis

FRD:

fumarate reductase

gRNAs:

short transcripts RNA

HAT:

Human African Trypanosomiasis

kDNA:

kinetoplastid DNA

MMP:

mitochondrial membrane potential

NADH:

nicotinamide adenine dinucleotide

NTDs:

neglected tropical diseases

PCD:

programmed cell death

RIC:

rNA import complex

ROS:

reactive oxygen species

TAO:

Trypanosoma alternative oxidase

tRNA:

transcription DNA

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  1. Departamento de Parasitología, Instituto de Medicina Tropical “Pedro Kourí”, Apartado Postal No. 601, Marianao 13, Ciudad Habana, Cuba

    Lianet Monzote Fidalgo

  2. Institute of Pharmacology and Toxicology Department of Biomedical Sciences, University of Veterinary Medicine, Veterinärplatz 1, 1210, Vienna, Austria

    Lars Gille

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Fidalgo, L.M., Gille, L. Mitochondria and Trypanosomatids: Targets and Drugs. Pharm Res 28, 2758–2770 (2011). https://doi.org/10.1007/s11095-011-0586-3

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