Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Understanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used approach to study host‐pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmod...

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Published in:Chembiochem : a European journal of chemical biology 2024-08, Vol.25 (15), p.e202400187-n/a
Main Authors: Iacobucci, Ilaria, Monaco, Vittoria, Hovasse, Agnès, Dupouy, Baptiste, Keumoe, Rodrigue, Cichocki, Bogdan, Elhabiri, Mourad, Meunier, Brigitte, Strub, Jean‐Marc, Monti, Maria, Cianférani, Sarah, Blandin, Stéphanie A., Schaeffer‐Reiss, Christine, Davioud‐Charvet, Elisabeth
Format: Article
Language:English
Subjects:
Activity-Based Protein Profiling
Affinity
Antiprotozoal agents
Biological Chemistry and Chemical Biology
Blood parasites
Chemical synthesis
Drug development
Drug resistance
Localization
Menadione
Metabolites
Molecular modelling
Oxidoreductase
Parasite resistance
Parasites
Photoaffinity Labeling
Probes
Proteins
Proteomes
Proteomics
Toxicity
Yeast
Yeasts
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Summary:Understanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used approach to study host‐pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmodial early‐lead drug exerting potent activities against young asexual and sexual blood stages in vitro with low toxicity to host cells. To elucidate its molecular mechanisms, an affinity‐based protein profiling (AfBPP) approach was applied to yeast and P. falciparum proteomes. New (pro‐) AfBPP probes based on the 3‐benz(o)yl‐6‐fluoro‐menadione scaffold were synthesized. With optimized conditions of both photoaffinity labeling and click reaction steps, the AfBPP protocol was then applied to a yeast proteome, yielding 11 putative drug‐protein targets. Among these, we found four proteins associated with oxidoreductase activities, the hypothesized type of targets for plasmodione and its metabolites, and other proteins associated with the mitochondria. In Plasmodium parasites, the MS analysis revealed 44 potential plasmodione targets that need to be validated in further studies. Finally, the localization of a 3‐benzyl‐6‐fluoromenadione AfBPP probe was studied in the subcellular structures of the parasite at the trophozoite stage. We describe here the design, synthesis and evaluation of an antiplasmodial 3‐benzyl‐6‐fluoro‐menadione probe for affinity‐based protein profiling experiments using yeast and P. falciparum parasite lysates. These studies allowed us to identify a first list of proteins interacting with plasmodione in both yeast and P. falciparum late trophozoites.
ISSN:1439-4227
1439-7633
1439-7633
DOI:10.1002/cbic.202400187