Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub>
Previous investigations of the <i>Leishmania infantum</i> 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 R...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/18/5890 |
| _version_ | 1827658416838934528 |
|---|---|
| author | Yosser Zina Abdelkrim Emna Harigua-Souiai Imen Bassoumi-Jamoussi Mourad Barhoumi Josette Banroques Khadija Essafi-Benkhadir Michael Nilges Arnaud Blondel N. Kyle Tanner Ikram Guizani |
| author_facet | Yosser Zina Abdelkrim Emna Harigua-Souiai Imen Bassoumi-Jamoussi Mourad Barhoumi Josette Banroques Khadija Essafi-Benkhadir Michael Nilges Arnaud Blondel N. Kyle Tanner Ikram Guizani |
| author_sort | Yosser Zina Abdelkrim |
| collection | DOAJ |
| description | Previous investigations of the <i>Leishmania infantum</i> 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-<i>Leishmania</i> activity on <i>L. infantum</i> promastigotes. Additionally, docking simulations explained the importance of the double bond between C5 and C6 in 7-<i>α</i>-aminocholesterol and the amino group in the C7 position. In conclusion, <i>Leishmania</i> and mammalian eIF4A proteins appeared to interact differently with effectors, thus making LieIF4A a potential drug against leishmaniases. |
| first_indexed | 2024-03-09T23:02:25Z |
| format | Article |
| id | doaj.art-dd3b2dc394d34a8a8f9fc27de5aab333 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:02:25Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-dd3b2dc394d34a8a8f9fc27de5aab3332023-11-23T18:00:38ZengMDPI AGMolecules1420-30492022-09-012718589010.3390/molecules27185890Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub>Yosser Zina Abdelkrim0Emna Harigua-Souiai1Imen Bassoumi-Jamoussi2Mourad Barhoumi3Josette Banroques4Khadija Essafi-Benkhadir5Michael Nilges6Arnaud Blondel7N. Kyle Tanner8Ikram Guizani9Laboratory of Molecular Epidemiology and Experimental Pathology (LR11IPT04/LR16IPT04)/Laboratory of Epidemiology and Ecology of Parasites, Institut Pasteur de Tunis—University Tunis El Manar, Tunis 1002, TunisiaLaboratory of Molecular Epidemiology and Experimental Pathology (LR11IPT04/LR16IPT04)/Laboratory of Epidemiology and Ecology of Parasites, Institut Pasteur de Tunis—University Tunis El Manar, Tunis 1002, TunisiaLaboratory of Molecular Epidemiology and Experimental Pathology (LR11IPT04/LR16IPT04)/Laboratory of Epidemiology and Ecology of Parasites, Institut Pasteur de Tunis—University Tunis El Manar, Tunis 1002, TunisiaLaboratory of Molecular Epidemiology and Experimental Pathology (LR11IPT04/LR16IPT04)/Laboratory of Epidemiology and Ecology of Parasites, Institut Pasteur de Tunis—University Tunis El Manar, Tunis 1002, TunisiaUniversité de Paris Cité & CNRS, Expression Génétique Microbienne, Institut de Biologie Physico-Chimique, 13 Rue Pierre et Marie Curie, F-75005 Paris, FranceLaboratory of Molecular Epidemiology and Experimental Pathology (LR11IPT04/LR16IPT04)/Laboratory of Epidemiology and Ecology of Parasites, Institut Pasteur de Tunis—University Tunis El Manar, Tunis 1002, TunisiaStructural Bioinformatics Unit, Institut Pasteur, F-75015 Paris, FranceStructural Bioinformatics Unit, Institut Pasteur, F-75015 Paris, FranceUniversité de Paris Cité & CNRS, Expression Génétique Microbienne, Institut de Biologie Physico-Chimique, 13 Rue Pierre et Marie Curie, F-75005 Paris, FranceLaboratory of Molecular Epidemiology and Experimental Pathology (LR11IPT04/LR16IPT04)/Laboratory of Epidemiology and Ecology of Parasites, Institut Pasteur de Tunis—University Tunis El Manar, Tunis 1002, TunisiaPrevious investigations of the <i>Leishmania infantum</i> 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-<i>Leishmania</i> activity on <i>L. infantum</i> promastigotes. Additionally, docking simulations explained the importance of the double bond between C5 and C6 in 7-<i>α</i>-aminocholesterol and the amino group in the C7 position. In conclusion, <i>Leishmania</i> and mammalian eIF4A proteins appeared to interact differently with effectors, thus making LieIF4A a potential drug against leishmaniases.https://www.mdpi.com/1420-3049/27/18/58907-α-aminocholesteroldrug designtranslation-initiation factorinhibitor<i>Leishmania infantum</i> |
| spellingShingle | Yosser Zina Abdelkrim Emna Harigua-Souiai Imen Bassoumi-Jamoussi Mourad Barhoumi Josette Banroques Khadija Essafi-Benkhadir Michael Nilges Arnaud Blondel N. Kyle Tanner Ikram Guizani Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub> Molecules 7-α-aminocholesterol drug design translation-initiation factor inhibitor <i>Leishmania infantum</i> |
| title | Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub> |
| title_full | Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub> |
| title_fullStr | Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub> |
| title_full_unstemmed | Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub> |
| title_short | Enzymatic and Molecular Characterization of Anti-<i>Leishmania</i> Molecules That Differently Target <i>Leishmania</i> and Mammalian eIF4A Proteins, LieIF4A and eIF4A<sub>Mus</sub> |
| title_sort | enzymatic and molecular characterization of anti i leishmania i molecules that differently target i leishmania i and mammalian eif4a proteins lieif4a and eif4a sub mus sub |
| topic | 7-α-aminocholesterol drug design translation-initiation factor inhibitor <i>Leishmania infantum</i> |
| url | https://www.mdpi.com/1420-3049/27/18/5890 |
| work_keys_str_mv | AT yosserzinaabdelkrim enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT emnahariguasouiai enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT imenbassoumijamoussi enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT mouradbarhoumi enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT josettebanroques enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT khadijaessafibenkhadir enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT michaelnilges enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT arnaudblondel enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT nkyletanner enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub AT ikramguizani enzymaticandmolecularcharacterizationofantiileishmaniaimoleculesthatdifferentlytargetileishmaniaiandmammalianeif4aproteinslieif4aandeif4asubmussub |