Proteomic Profiling of Antimalarial Plasmodione Using 3-Benz(o)ylmenadione Affinity-Based Probes.
Fiche publication
Date publication
avril 2024
Journal
Chembiochem : a European journal of chemical biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah, Mme SCHAEFFER-REISS Christine, Dr DAVIOUD-CHARVET Elisabeth , Dr ELHABIRI Mourad
Tous les auteurs :
Iacobucci I, Monaco V, Hovasse A, Dupouy B, Keumoe R, Cichocki B, Elhabiri M, Meunier B, Strub JM, Monti M, Cianférani S, Blandin SA, Schaeffer-Reiss C, Davioud-Charvet E
Lien Pubmed
Résumé
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.
Mots clés
Activity-Based Protein Profiling * Antiprotozoal agents * Biological Chemistry and Chemical Biology * Photoaffinity Labeling * Proteomics
Référence
Chembiochem. 2024 04 19;:e202400187