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Proteomic Profiling of Antimalarial Plasmodione Using 3-Benz(o)ylmenadione Affinity-Based Probes
Ilaria Iacobucci1,2,3,4, Vittoria Monaco1,2,3,4, Agnès Hovasse2,3
1Laboratoire d'Innovation Moléculaire et Applications (LIMA), Team Bio(IN)organic & Medicinal Chemistry, UMR7042 CNRS-Université de Strasbourg-Université Haute-Alsace, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, 25, rue Becquerel, F-67087, Strasbourg, France.
This study used affinity-based protein profiling to identify how the anti-malarial drug plasmodione works. Researchers found potential drug targets in yeast and Plasmodium parasites, aiding new drug development against malaria.
Area of Science:
- Biochemistry
- Parasitology
- Drug Discovery
Background:
- Understanding drug mechanisms is vital for developing new anti-malarial drugs and overcoming resistance.
- Proteomics offers a powerful approach to investigate host-pathogen interactions and pinpoint drug targets.
- Plasmodione is a promising anti-malarial compound effective against various parasite stages with low host cell toxicity.
Purpose of the Study:
- To elucidate the molecular targets and mechanisms of action of the anti-malarial drug plasmodione.
- To apply affinity-based protein profiling (AfBPP) to identify plasmodione's protein targets in yeast and Plasmodium falciparum.
- To synthesize and utilize novel AfBPP probes based on the 3-benz(o)yl-6-fluoro-menadione scaffold.
Main Methods:
- Synthesis of new (pro-) AfBPP probes.
- Optimization of photoaffinity labeling and click reaction conditions.
- Application of AfBPP to yeast and Plasmodium proteomes followed by mass spectrometry (MS) analysis.
- Subcellular localization studies of AfBPP probes in P. falciparum.
Main Results:
- In yeast, 11 putative drug-protein targets were identified, including four oxidoreductase-associated proteins and mitochondrial proteins.
- Mass spectrometry analysis in Plasmodium parasites revealed 44 potential plasmodione targets requiring further validation.
- Localization studies indicated the probe's presence within the parasite's subcellular structures at the trophozoite stage.
Conclusions:
- AfBPP is an effective method for identifying drug targets in both model organisms and malaria parasites.
- The identified targets, particularly oxidoreductases, provide insights into plasmodione's mechanism of action.
- This research contributes to the development of novel anti-malarial therapies by identifying potential drug targets.
