Discovery and Genetic Validation of Chemotherapeutic Targets for Chagas' Disease

Abstract

There is an urgent need to develop new treatments for Chagas' disease. To identify drug targets, it is important to understand the basic biology of Trypanosoma cruzi, in particular with respect to the biological pathways or proteins that are essential for its survival within the host. This review provides a streamlined approach for identifying drug targets using freely available chemogenetic databases and outlines the relevant characteristics of an ideal chemotherapeutic target. Among those are their essentiality, druggability, availability of structural information, and selectivity. At the moment only 16 genes have been found as essential by gene disruption in T. cruzi. At the TDR Targets database, a chemogenomics resource for neglected diseases, information about published structures for these genes was only found for three of these genes, and annotation of validated inhibitors was found in two. These inhibitors have activity against the parasitic stages present in the host. We then analyzed three of the pathways that are considered promising in the search for new targets: (1) Ergosterol biosynthesis, (2) Resistance to oxidative stress, (3) Synthesis of surface glycoconjugates. We have annotated all the genes that participate in them, identified those that are considered as druggable, and incorporated evidence from either Trypanosoma brucei, and Leishmania spp. that supports the hypothesis that these pathways are essential for T. cruzi survival.

The efficacy of new 2,5-dihydroxybenzyl derivatives against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis

“…The first stage in the discovery or repurposing of antimicrobial agents is target identification. It usually involves the screening of collections of compounds against a molecular target, typically an enzyme (targetbased screening), or against whole organisms (cellbased or phenotypic screening) [51]. All candidates must then be refined through a cyclical process of structure modifications, until they achieve significant activity, typically in an animal model of infection.…”

“…All candidates must then be refined through a cyclical process of structure modifications, until they achieve significant activity, typically in an animal model of infection. Subsequently, the biological activity, pharmacokinetics, and safety profile of the series are optimized by a process that leads to the selection of candidate drugs [51]. Selected drugs are then submitted to a process of regulatory toxicology and scale-up that enables their evaluation in human studies [52].…”

The Endless Frontier? The Recent Upsurge of R&D Productivity in Pharmaceuticals

“…Indeed, the extensive genetic validation of drug targets has been shown to improve the chances of passing through clinical stages 32 and has become more widely embraced in different therapeutic areas. 33,34 A better selection of patient subsets for the clinical trials via "stratification" based on biomarkers 36 is another possible factor of improvement of success rates. Also, the prevalence of antibodies as new drugs has simplified both preclinical development and clinical grade batch preparation, since antibody production is a relatively easy process amongst biologics.…”

Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites

“…So far, 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 ]. The few targets that have been suggested for Trypanosoma brucei and T. cruzi have only been partially characterized [ 8 , 9 , 10 , 11 , 12 ] and ornithine decarboxylase is currently the only fully validated target involved in the mode-of-action (MoA) of eflornithine [ 8 , 13 ]. Identification of novel drug ‘leads’ is generally still achieved by phenotypic cell-based screening [ 14 , 15 , 16 , 17 ] but with the disadvantage of lack of knowledge gained on the MoA.…”