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; Paunescu, Emilia; Braga, Sophie Marie-Pierre; Heller, Manfred; Furrer, Julien; Hemphill, Andrew (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(19) Molecular Diversity Preservation International MDPI 10.3390/ijms221910787

[img]
Preview
Text
Anghel_et_al_ijms-22-10787-v2.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (8MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Massenspektrometrie- und Proteomics-Labor

UniBE Contributor:

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

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
600 Technology > 610 Medicine & health

ISSN:

1661-6596

Publisher:

Molecular Diversity Preservation International MDPI

Language:

English

Submitter:

Andrew Hemphill

Date Deposited:

22 Oct 2021 11:07

Last Modified:

22 Oct 2021 11:07

Publisher DOI:

10.3390/ijms221910787

PubMed ID:

34639127

Uncontrolled Keywords:

ATP-synthase affinity chromatography binding proteins metabolism mitochondrion proteomics

BORIS DOI:

10.48350/160247

URI:

https://boris.unibe.ch/id/eprint/160247

Actions (login required)

Edit item Edit item
Provide Feedback