Enzymatic and Molecular Characterization of Anti-Leishmania Molecules That Differently Target Leishmania and Mammalian eIF4A Proteins, LieIF4A and eIF4AMus - Institut Pasteur de Tunis Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2022

Enzymatic and Molecular Characterization of Anti-Leishmania Molecules That Differently Target Leishmania and Mammalian eIF4A Proteins, LieIF4A and eIF4AMus

Résumé

Previous investigations of the Leishmania infantum eIF4A-like protein (LieIF4A) as a potential drug target delivered cholestanol derivatives inhibitors. Here, we investigated the mode of action of cholesterol derivatives as a novel scaffold structure of LieIF4A inhibitors on the RNA-dependent ATPase activity of LieIF4A and its mammalian ortholog (eIF4AI). We compared their biochemical effects on RNA-dependent ATPase activities of both proteins and investigated if rocaglamide, a known inhibitor of eIF4A, could affect LieIF4A as well. Kinetic measurements were conducted at different concentrations of ATP, of the compound and in the presence of saturating whole yeast RNA concentrations. Kinetic analyses showed different ATP binding affinities for the two enzymes as well as different sensitivities to 7-α-aminocholesterol and rocaglamide. The 7-α-aminocholesterol inhibited LieIF4A with a higher binding affinity relative to cholestanol analogs. Cholesterol, another tested sterol, had no effect on the ATPase activity of LieIF4A or eIF4AI. The 7-α-aminocholesterol demonstrated an anti-Leishmania activity on L. infantum promastigotes. Additionally, docking simulations explained the importance of the double bond between C5 and C6 in 7-α-aminocholesterol and the amino group in the C7 position. In conclusion, Leishmania and mammalian eIF4A proteins appeared to interact differently with effectors, thus making LieIF4A a potential drug against leishmaniases
Fichier principal
Vignette du fichier
Zina_molecules-27-05890.pdf (1.7 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03813436 , version 1 (13-10-2022)

Licence

Paternité

Identifiants

Citer

Yosser Zina Abdelkrim, Emna Harigua-Souiai, Imen Bassoumi-Jamoussi, Mourad Barhoumi, Josette Banroques, et al.. Enzymatic and Molecular Characterization of Anti-Leishmania Molecules That Differently Target Leishmania and Mammalian eIF4A Proteins, LieIF4A and eIF4AMus. Molecules, 2022, 27 (18), pp.5890. ⟨10.3390/molecules27185890⟩. ⟨hal-03813436⟩
16 Consultations
11 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More