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Article

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

1
Institute of Parasitology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
2
Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland
3
Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland
4
Proteomics and Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Bern, 3012 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Academic Editors: Antonello Merlino and Giarita Ferraro
Int. J. Mol. Sci. 2021, 22(19), 10787; https://doi.org/10.3390/ijms221910787
Received: 10 September 2021 / Revised: 29 September 2021 / Accepted: 2 October 2021 / Published: 5 October 2021
Toxoplasma gondii is an apicomplexan parasite that infects and proliferates within many different types of host cells and infects virtually all warm-blooded animals and humans. Trypanosoma brucei is an extracellular kinetoplastid that causes human African trypanosomiasis and Nagana disease in cattle, primarily in rural sub-Saharan Africa. Current treatments against both parasites have limitations, e.g., suboptimal efficacy and adverse side effects. Here, we investigate the potential cellular and molecular targets of a trithiolato-bridged arene ruthenium complex conjugated to 9-(2-hydroxyethyl)-adenine (1), which inhibits both parasites with IC50s below 10−7 M. Proteins that bind to 1 were identified using differential affinity chromatography (DAC) followed by shotgun-mass spectrometry. A trithiolato-bridged ruthenium complex decorated with hypoxanthine (2) and 2-hydroxyethyl-adenine (3) were included as controls. Transmission electron microscopy (TEM) revealed distinct ultrastructural modifications in the mitochondrion induced by (1) but not by (2) and (3) in both species. DAC revealed 128 proteins in T. gondii and 46 proteins in T. brucei specifically binding to 1 but not 2 or 3. In T. gondii, the most abundant was a protein with unknown function annotated as YOU2. This protein is a homolog to the human mitochondrial inner membrane translocase subunit Tim10. In T. brucei, the most abundant proteins binding specifically to 1 were mitochondrial ATP-synthase subunits. Exposure of T. brucei bloodstream forms to 1 resulted in rapid breakdown of the ATP-synthase complex. Moreover, both datasets contained proteins involved in key steps of metabolism and nucleic acid binding proteins. View Full-Text
Keywords: mitochondrion; affinity chromatography; binding proteins; ATP-synthase; proteomics; metabolism mitochondrion; affinity chromatography; binding proteins; ATP-synthase; proteomics; metabolism
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    Doi: 10.5281/zenodo.5500094
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    Description: Suppl. files to: Cellular and molecular targets of nucleotide-tagged trithiola-to-bridged arene ruthenium complexes in the protozoan para-sites Toxoplasma gondii and Trypanosoma brucei
MDPI and ACS Style

Anghel, N.; Müller, J.; Serricchio, M.; Jelk, J.; Bütikofer, P.; Boubaker, G.; Imhof, D.; Ramseier, J.; Desiatkina, O.; Păunescu, E.; Braga-Lagache, S.; Heller, M.; Furrer, J.; Hemphill, A. Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei. Int. J. Mol. Sci. 2021, 22, 10787. https://doi.org/10.3390/ijms221910787

AMA Style

Anghel N, Müller J, Serricchio M, Jelk J, Bütikofer P, Boubaker G, Imhof D, Ramseier J, Desiatkina O, Păunescu E, Braga-Lagache S, Heller M, Furrer J, Hemphill A. Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei. International Journal of Molecular Sciences. 2021; 22(19):10787. https://doi.org/10.3390/ijms221910787

Chicago/Turabian Style

Anghel, Nicoleta, Joachim Müller, Mauro Serricchio, Jennifer Jelk, Peter Bütikofer, Ghalia Boubaker, Dennis Imhof, Jessica Ramseier, Oksana Desiatkina, Emilia Păunescu, Sophie Braga-Lagache, Manfred Heller, Julien Furrer, and Andrew Hemphill. 2021. "Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei" International Journal of Molecular Sciences 22, no. 19: 10787. https://doi.org/10.3390/ijms221910787

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