Omics data integration facilitates target selection for new antiparasitic drugs against TriTryp infections

Abstract

Introduction:Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp., commonly referred to as TriTryps, are a group of protozoan parasites that cause important human diseases affecting millions of people belonging to the most vulnerable populations worldwide. Current treatments have limited efficiencies and can cause serious side effects, so there is an urgent need to develop new control strategies. Presently, the identification and prioritization of appropriate targets can be aided by integrative genomic and computational approaches.Methods: In this work, we conducted a genome-wide multidimensional data integration strategy to prioritize drug targets. We included genomic, transcriptomic, metabolic, and protein structural data sources, to delineate candidate proteins with relevant features for target selection in drug development.Results and Discussion: Our final ranked list includes proteins shared by TriTryps and covers a range of biological functions including essential proteins for parasite survival or growth, oxidative stress-related enzymes, virulence factors, and proteins that are exclusive to these parasites. Our strategy found previously described candidates, which validates our approach as well as new proteins that can be attractive targets to consider during the initial steps of drug discovery.

Metallomics: An Essential Tool for the Study of Potential Antiparasitic Metallodrugs

“… 63 Furthermore, other authors have conducted a genome-wide multidimensional data integration strategy including genomic, transcriptomic, metabolic, and protein structural data sources, to identify candidate proteins with relevant features for target selection in drug development against Trypanosoma cruzi , Trypanosoma brucei , and Leishmania spp , which gave rise to a list of 319 common candidates. 64 Other similar approaches have also been described in the past few years. 65 , 66 …”

“…For instance, a transcriptomic analysis of benznidazole-resistant and susceptible Trypanosoma cruzi populations was performed, generating a robust set of transcripts involved in different metabolic pathways associated with the benznidazole-resistant phenotype of the parasite, which is of utmost importance, since benznidazole is one of the two drugs currently approved for the treatment of the disease . Furthermore, other authors have conducted a genome-wide multidimensional data integration strategy including genomic, transcriptomic, metabolic, and protein structural data sources, to identify candidate proteins with relevant features for target selection in drug development against Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp , which gave rise to a list of 319 common candidates . Other similar approaches have also been described in the past few years. , …”

Possible Chemotherapeutic Potential of Inhibiting N-Alpha Terminal Acetylation Activities to Combat Trypanosome Infections

“…The efforts to find new drug targets against trypanosome infections are advancing, notably interference with the trypanothione metabolism pathway [142], calcium homeostasis, nucleoside analog targeting purine salvage pathway, and drug combination of low-cost molecules in T. cruzi [143,144]. Furthermore, it is now possible to perform in silico analysis to identify new drug targets in trypanosomes [14,145]. Several new molecular targets eligible for clinical trials have been identified [6].…”

“…Thus, high-throughput drug target identification using RNA interference is currently advancing [12]. Furthermore, integrative genomic and bioinformatics mining is possible, and can be used to facilitate target selection for new anti-Trypanosoma activities [13][14][15][16].…”