Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei

Anghel, Nicoleta; Müller, Joachim; Serricchio, Mauro; Jelk, Jennifer; Bütikofer, Peter; Boubaker, Ghalia; Imhof, Dennis; Ramseier, Jessica; Desiatkina, Oksana; Păunescu, Emilia; Braga-Lagache, Sophie; Heller, Manfred; Furrer, Julien; Hemphill, Andrew

doi:10.3390/ijms221910787

Cited by 20 publications

(22 citation statements)

References 40 publications

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“…In this study, under the pos ion mode (72 h), the amount of the substance was upregulated and involved in metabolic pathways and purine metabolism, which showed that the substance was of great significance to the normal physiology of cells. It has been reported that Toxoplasma gondii cannot synthesize purine, and it is very dependent on the enzymes and intermediates in the purine salvage pathway [ 63 ]. The purines of infected cells are upregulated after being treated with drugs, so we speculate that T. annulata may not have the ability to synthesize purines, and thus they will be upregulated after parasite removal.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling of bovine leucocytes transformed by Theileria annulata under BW720c treatment

Zhao

Liu

et al. 2022

Parasites Vectors

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Background When Theileria annulata infects host cells, it undertakes unlimited proliferation as tumor cells. Although the transformed cells will recover their limited reproductive characteristics and enter the apoptosis process after treatment with buparvaquone (BW720c), the metabolites and metabolic pathways involved are not clear. Methods The transformed cells of T. annulata were used as experimental materials, and the buparvaquone treatment group and DMSO control group were used. Qualitative and quantitative analysis was undertaken of 36 cell samples based on the LC–QTOF platform in positive and negative ion modes. The metabolites of the cell samples after 72 h of drug treatment were analyzed, as were the different metabolites and metabolic pathways involved in the BW720c treatment. Finally, the differential metabolites and metabolic pathways in the transformed cells were found. Results A total of 1425 metabolites were detected in the negative ion mode and 1298 metabolites were detected in the positive ion mode. After drug treatment for 24 h, 48 h, and 72 h, there were 56, 162, and 243 differential metabolites in negative ion mode, and 35, 121, and 177 differential metabolites in positive ion mode, respectively. These differential metabolites are mainly concentrated on various essential amino acids. Conclusion BW720c treatment induces metabolic disturbances in T. annulata-infected cells by regulating the metabolism of leucine, arginine, and l-carnitine, and induces host cell apoptosis. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Metabolomic profiling of bovine leucocytes transformed by Theileria annulata under BW720c treatment

Zhao

Liu

et al. 2022

Parasites Vectors

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“…Then, the columns were separated, and the binding proteins were eluted with 50 mM acetic acid (5 mL per column). The eluates were lyophilized and stored at −80 • C [45].…”

Section: Protein Extraction and Affinity Chromatographymentioning

confidence: 99%

Common Molecular Targets of a Quinolone Based Bumped Kinase Inhibitor in Neospora caninum and Danio rerio

Müller

Anghel

Imhof

et al. 2022

IJMS

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Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii, and causes abortions, stillbirths and/or fetal malformations in livestock. Target-based drug development has led to the synthesis of calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs). Previous studies have shown that several BKIs have excellent efficacy against neosporosis in vitro and in vivo. However, several members of this class of compounds impair fertility in pregnant mouse models and cause embryonic malformation in a zebrafish (Danio rerio) model. Similar to the first-generation antiprotozoal drug quinine, some BKIs have a quinoline core structure. To identify common targets in both organisms, we performed differential affinity chromatography with cell-free extracts from N. caninum tachyzoites and D. rerio embryos using the 5-aminopyrazole-4-carboxamide (AC) compound BKI-1748 and quinine columns coupled to epoxy-activated sepharose followed by mass spectrometry. BKI-binding proteins of interest were identified in eluates from columns coupled to BKI-1748, or in eluates from BKI-1748 as well as quinine columns. In N. caninum, 12 proteins were bound specifically to BKI-1748 alone, and 105 proteins, including NcCDPK1, were bound to both BKI-1748 and quinine. For D. rerio, the corresponding numbers were 13 and 98 binding proteins, respectively. In both organisms, a majority of BKI-1748 binding proteins was involved in RNA binding and modification, in particular, splicing. Moreover, both datasets contained proteins involved in DNA binding or modification and key steps of intermediate metabolism. These results suggest that BKI-1748 interacts with not only specific targets in apicomplexans, such as CDPK1, but also with targets in other eukaryotes, which are involved in common, essential pathways.

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“…Moreover, the potential cellular and molecular targets of conjugate 14 were recently investigated 124 .…”

Section: Assessment Of the In Vitro Activity Against T Gondii β-Gal A...mentioning

confidence: 99%

New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Desiatkina

Mösching

Anghel

et al. 2022

Preprint

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Aiming to generate novel compounds with improved antitoxoplama activity by exploiting the parasite auxotrophies, a library of nucleic base-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates - was synthesized and evaluated. Various structural features as the nucleobase (adenine, uracil, cytosine, thymine, and xanthine) and the linker between the two units were progressively modified. To substantiate the concept, hybrid molecules comprising the diruthenium moiety and other type of pendant molecules were also synthesized and assessed. The use of the CuAAC (copper catalyzed azide-alkyne cycloaddition) approach for the obtainment of conjugates bearing the trithiolato diruthenium scaffold was validated. 37 Compounds (diruthenium conjugates and corresponding intermediates) were assessed in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 μM. In parallel the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. 20 Compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal dose-response studies (IC50, half maximal inhibitory concentration determination) and their toxicity for HFF was assessed at 2.5 μM. Two compounds showing promise for further development were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC50 values of 0.059 and 0.111 μM respectively, significantly lower compared to the standard drug pyrimethamine (IC50 = 0.326 μM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 μM and are candidates as potential treatment options in a suitable in vivo model.

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Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei

Cited by 20 publications

References 40 publications

Metabolomic profiling of bovine leucocytes transformed by Theileria annulata under BW720c treatment

Metabolomic profiling of bovine leucocytes transformed by Theileria annulata under BW720c treatment

Common Molecular Targets of a Quinolone Based Bumped Kinase Inhibitor in Neospora caninum and Danio rerio

New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

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