Glycosomal Targets for Anti-Trypanosomatid Drug Discovery

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.

Targeting pathogen metabolism without collateral damage to the host

“…Although inhibitors of T. brucei GAPDH exist13, for a stringent test of the network-based selectivity we decided to target glucose transport. This target has the advantage drug uptake is not required.…”

“…However, T. brucei glycolysis does not contain unique parasitic proteins (although some are evolutionary and structurally distant from their human counterparts (see ref. 13 and references therein). Moreover, glycolysis is also essential for many human cell types.…”

“…Only 50% inhibition of glycolysis is sufficient to kill trypanosomes12, which makes it a potent target pathway for antitrypanosomal drugs. Structural differences between human and trypanosome glycolytic enzymes make some of them attractive as drug targets13. Nevertheless, since glycolysis is also vital for the human host’s cells, drug selectivity remains a critical challenge.…”

Discovery of Sustainable Drugs for Neglected Tropical Diseases: Cashew Nut Shell Liquid (CNSL)‐Based Hybrids Target Mitochondrial Function and ATP Production in Trypanosoma brucei

“…In particular, building on the strategy that the combinations of two different fragments into one covalently linked hybrid compound can convey synergy and increase potency, we combined the chemical features of CNSL derivatives with those of a previously developed anti‐trypanosomal hit compound ( 4 in Figure ) . Intriguingly, both 4 and a mixture of anacardic acids, isolated from Brazilian CNSL, have been reported to inhibit trypanosomal glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), an essential glycolytic enzyme and a validated anti‐trypanosomatid target …”

New drugs with antiprotozoal activity from marine algae: a review

“…The glycosomal targets for anti-trypanosomatid drug discovery have been reviewed recently (Barros-Alvarez et al, 2013). Despite the efforts to find new drugs against Leishmania spp., the treatment of leishmaniasis is still based on the use of pentavalent antimonials (sodium stibogluconate and meglumine antimoniate), developed more than 60 years ago and are known to have several notable side effects, including nausea, abdominal colic, diarrhea, skin rashes, hepatotoxicity and cardiotoxicity.…”