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. 2023 Apr 6:14:1136321.
doi: 10.3389/fphar.2023.1136321. eCollection 2023.

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

Martin Rivara-Espasandín  1   2 , Miranda Clara Palumbo  3   4 , Ezequiel J Sosa  4   5 , Santiago Radío  1 , Adrián G Turjanski  4   5 , José Sotelo-Silveira  1   6 , Dario Fernandez Do Porto  3   4 , Pablo Smircich  1   6
Affiliations

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

Martin Rivara-Espasandín et al. Front Pharmacol. .

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.

Keywords: drug discovery; genomics; neglected disease; target selection; trypanosomatids.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Distribution of protein Druggability Scores (DSs) and Human Off-Target Scores (HOT) in each of the parasites (A) Density plots showing the distribution of DSs ​​for Trypanosoma cruzi, Trypanosoma brucei, Leishmania major proteins as well as the complete PDB database for comparison (B) Density plots showing the distribution of HOT for Trypanosoma cruzi, Trypanosoma brucei and Leishmania major proteins.
FIGURE 2
FIGURE 2
Selection of common drug target candidates in TriTryps (A) Clusters obtained by using MMseqs2. Venn diagram representing the intersection of similar genes for the three parasites (B) Potential drug targets common to Trypanosoma cruzi, Trypanosoma brucei and Leishmania major. Each circle depicts the number of proteins obtained after applying the indicated filter. Orange: 3,333 common clusters for the three parasites. Gray: 907 common clusters where the three proteins have a DS ≥ 0.5. Yellow: 319 common clusters where the three proteins also have a HOT ≥ 0.7.
FIGURE 3
FIGURE 3
Candidate genes expression in life cycle stages. Box plots showing the mRNA levels of the total genes (T) and of our drug target candidates (C) in (A) T. Cruzi trypomastigotes (T) and amastigotes (AMA) (B) Trypanosoma brucei slender (SL) and stumpy (ST) forms of blood trypomastigotes and (C) Leishmania major metacyclic promastigotes (MP) and amastigotes (AMA). Mann–Whitney–Wilcoxon test was performed to compare the different gene sets [p-value <0.001 (***); p-value <0.05 (*); no significance (NS.)]. Only expressed genes are plotted (see Materials and Methods).
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Grants and funding

Fellowship supported from CONICET to MP. DF, ES and AT are members of CONICET. This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, PICT-2018-04663 to DF, ES and AT) and Universidad de Buenos Aires (20020190200275BA to DF). PS and JS-S received financial support from PEDECIBA and are members of ANII research career.