Glycosomal Targets for Anti-Trypanosomatid Drug Discovery

X.      Barros-Alvarez; M.      Gualdron-Lopez; H.      Acosta; A.J.      Caceres; M.A.S.      Graminha; P.A.M.      Michels; J.L.      Concepcion; W.      Quinones

Abstract

Glycosomes are peroxisome-related organelles found in all kinetoplastid protists, including the human pathogenic species of the family Trypanosomatidae: Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Glycosomes are unique in containing the majority of the glycolytic/gluconeogenic enzymes, but they also possess enzymes of several other important catabolic and anabolic pathways. The different metabolic processes are connected by shared cofactors and some metabolic intermediates, and their relative importance differs between the parasites or their distinct lifecycle stages, dependent on the environmental conditions encountered. By genetic or chemical means, a variety of glycosomal enzymes participating in different processes have been validated as drug targets. For several of these enzymes, as well as others that are likely crucial for proliferation, viability or virulence of the parasites, inhibitors have been obtained by different approaches such as compound libraries screening or design and synthesis. The efficacy and selectivity of some initially obtained inhibitors of parasite enzymes were further optimized by structure-activity relationship analysis, using available protein crystal structures. Several of the inhibitors cause growth inhibition of the clinically relevant stages of one or more parasitic trypanosomatid species and in some cases exert therapeutic effects in infected animals. The integrity of glycosomes and proper compartmentalization of at least several matrix enzymes is also crucial for the viability of the parasites. Therefore, proteins involved in the assembly of the organelles and transmembrane passage of substrates and products of glycosomal metabolism offer also promise as drug targets. Natural products with trypanocidal activity by affecting glycosomal integrity have been reported.

Keywords: Drug target validation, enzyme inhibitors, glycolysis, glycosomes, metabolic compartmentalization, oxidative stress defence, pentosephosphate pathway, protein import, purine salvage, sterol synthesis, solute translocation, Trypanosomatidae.