Selection of Molecular Targets for Drug Development Against Trypanosomatids

Abstract

Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

Inositol transport proteins

“…More than 27 million people worldwide are affected by diseases caused by trypanosomatid parasites, mainly Leishmania or Trypanosoma species [89]. Protozoan inositol transporters are potential targets for medication.…”

Chagas Disease Drug Discovery: Toward a New Era

“…104 Target deconvolution using omics, bioinformatics and genetic technologies, applied to T. cruzi could lead to target-based strategies to identify new chemical starting points; they could also give important information related to potential safety issues or identify specific markers to look at during further development. [105][106][107][108] In Vivo Experimental Animal Models Although a consensus for in vivo animal models was published in 2010, 66 the lack of predictability of these models, as observed for the azoles that went into clinical trials, indicate a need to review these models. There is considerable variation depending on animal species, parasite strain, and readouts used, to cite only a few issues to challenge their adequacy.…”

Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity

“…A variety of molecular targets has been identified for designing new drugs, among which are metabolites formed during sterol biosynthesis, glycolysis, and DNA synthesis . An important characteristic of T. cruzi is its dependence on glycolysis as an energy source for cellular survival .…”