Fiche publication
Date publication
mai 2021
Journal
JACS Au
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah
,
Mme SCHAEFFER-REISS Christine
,
Dr DAVIOUD-CHARVET Elisabeth
,
Dr ELHABIRI Mourad
Tous les auteurs :
Cichocki BA, Khobragade V, Donzel M, Cotos L, Blandin S, Schaeffer-Reiss C, Cianférani S, Strub JM, Elhabiri M, Davioud-Charvet E
Lien Pubmed
Résumé
Plasmodione () is a potent antimalarial redox-active drug acting at low nM range concentrations on different malaria parasite stages. In this study, in order to determine the precise protein interactome in parasites, we developed a class of (pro-)activity-based protein profiling probes (ABPP) as precursors of photoreactive benzophenone-like probes based on the skeleton of metabolites () generated in a cascade of redox reactions. Under UV-photoirradiation, we clearly demonstrate that benzylic oxidation of 3-benzylmenadione produces the 3-benzoylmenadione probe , allowing investigation of the proof-of-concept of the ABPP strategy with 3-benzoylmenadiones -. The synthesized 3-benzoylmenadiones, probe with an alkyne group or probe with -NO in position of the benzoyl chain, were found to be the most efficient photoreactive and clickable probes. In the presence of various H-donor partners, the UV-irradiation of the photoreactive ABPP probes generates different adducts, the expected "benzophenone-like" adducts (pathway 1) in addition to "benzoxanthone" adducts (via two other pathways, 2 and 3). Using both human and glutathione reductases, three protein ligand binding sites were identified following photolabeling with probes or . The photoreduction of 3-benzoylmenadiones ( and probe ) promoting the formation of both the corresponding benzoxanthone and the derived enone could be replaced by the glutathione reductase-catalyzed reduction step. In particular, the electrophilic character of the benzoxanthone was evidenced by its ability to alkylate heme, as a relevant event supporting the antimalarial mode of action of . This work provides a proof-of-principle that (pro-)ABPP probes can generate benzophenone-like metabolites enabling optimized activity-based protein profiling conditions that will be instrumental to analyze the interactome of early lead antiplasmodial 3-benzylmenadiones displaying an original and innovative mode of action.
Référence
JACS Au. 2021 May 24;1(5):669-689
