Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A.
Leishmaniases are neglected parasitic diseases in spite of the major burden they inflict on public health. The identification of novel drugs and targets constitutes a research priority. For that purpose we used Leishmania infantum initiation factor 4A (LieIF), an essential translation initiation fac...
Published in: | PLOS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:ebb7e2223ed14d3b805b46d2c9ede416 2023-05-15T15:10:30+02:00 Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. Emna Harigua-Souiai Yosser Zina Abdelkrim Imen Bassoumi-Jamoussi Ons Zakraoui Guillaume Bouvier Khadija Essafi-Benkhadir Josette Banroques Nathan Desdouits Hélène Munier-Lehmann Mourad Barhoumi N Kyle Tanner Michael Nilges Arnaud Blondel Ikram Guizani 2018-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006160 https://doaj.org/article/ebb7e2223ed14d3b805b46d2c9ede416 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5790279?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006160 https://doaj.org/article/ebb7e2223ed14d3b805b46d2c9ede416 PLoS Neglected Tropical Diseases, Vol 12, Iss 1, p e0006160 (2018) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2018 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006160 2022-12-31T03:26:02Z Leishmaniases are neglected parasitic diseases in spite of the major burden they inflict on public health. The identification of novel drugs and targets constitutes a research priority. For that purpose we used Leishmania infantum initiation factor 4A (LieIF), an essential translation initiation factor that belongs to the DEAD-box proteins family, as a potential drug target. We modeled its structure and identified two potential binding sites. A virtual screening of a diverse chemical library was performed for both sites. The results were analyzed with an in-house version of the Self-Organizing Maps algorithm combined with multiple filters, which led to the selection of 305 molecules. Effects of these molecules on the ATPase activity of LieIF permitted the identification of a promising hit (208) having a half maximal inhibitory concentration (IC50) of 150 ± 15 μM for 1 μM of protein. Ten chemical analogues of compound 208 were identified and two additional inhibitors were selected (20 and 48). These compounds inhibited the mammalian eIF4I with IC50 values within the same range. All three hits affected the viability of the extra-cellular form of L. infantum parasites with IC50 values at low micromolar concentrations. These molecules showed non-significant toxicity toward THP-1 macrophages. Furthermore, their anti-leishmanial activity was validated with experimental assays on L. infantum intramacrophage amastigotes showing IC50 values lower than 4.2 μM. Selected compounds exhibited selectivity indexes between 19 to 38, which reflects their potential as promising anti-Leishmania molecules. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 12 1 e0006160 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Emna Harigua-Souiai Yosser Zina Abdelkrim Imen Bassoumi-Jamoussi Ons Zakraoui Guillaume Bouvier Khadija Essafi-Benkhadir Josette Banroques Nathan Desdouits Hélène Munier-Lehmann Mourad Barhoumi N Kyle Tanner Michael Nilges Arnaud Blondel Ikram Guizani Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Leishmaniases are neglected parasitic diseases in spite of the major burden they inflict on public health. The identification of novel drugs and targets constitutes a research priority. For that purpose we used Leishmania infantum initiation factor 4A (LieIF), an essential translation initiation factor that belongs to the DEAD-box proteins family, as a potential drug target. We modeled its structure and identified two potential binding sites. A virtual screening of a diverse chemical library was performed for both sites. The results were analyzed with an in-house version of the Self-Organizing Maps algorithm combined with multiple filters, which led to the selection of 305 molecules. Effects of these molecules on the ATPase activity of LieIF permitted the identification of a promising hit (208) having a half maximal inhibitory concentration (IC50) of 150 ± 15 μM for 1 μM of protein. Ten chemical analogues of compound 208 were identified and two additional inhibitors were selected (20 and 48). These compounds inhibited the mammalian eIF4I with IC50 values within the same range. All three hits affected the viability of the extra-cellular form of L. infantum parasites with IC50 values at low micromolar concentrations. These molecules showed non-significant toxicity toward THP-1 macrophages. Furthermore, their anti-leishmanial activity was validated with experimental assays on L. infantum intramacrophage amastigotes showing IC50 values lower than 4.2 μM. Selected compounds exhibited selectivity indexes between 19 to 38, which reflects their potential as promising anti-Leishmania molecules. |
format |
Article in Journal/Newspaper |
author |
Emna Harigua-Souiai Yosser Zina Abdelkrim Imen Bassoumi-Jamoussi Ons Zakraoui Guillaume Bouvier Khadija Essafi-Benkhadir Josette Banroques Nathan Desdouits Hélène Munier-Lehmann Mourad Barhoumi N Kyle Tanner Michael Nilges Arnaud Blondel Ikram Guizani |
author_facet |
Emna Harigua-Souiai Yosser Zina Abdelkrim Imen Bassoumi-Jamoussi Ons Zakraoui Guillaume Bouvier Khadija Essafi-Benkhadir Josette Banroques Nathan Desdouits Hélène Munier-Lehmann Mourad Barhoumi N Kyle Tanner Michael Nilges Arnaud Blondel Ikram Guizani |
author_sort |
Emna Harigua-Souiai |
title |
Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. |
title_short |
Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. |
title_full |
Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. |
title_fullStr |
Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. |
title_full_unstemmed |
Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A. |
title_sort |
identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting leishmania eukaryotic translation initiation factor 4a. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2018 |
url |
https://doi.org/10.1371/journal.pntd.0006160 https://doaj.org/article/ebb7e2223ed14d3b805b46d2c9ede416 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 12, Iss 1, p e0006160 (2018) |
op_relation |
http://europepmc.org/articles/PMC5790279?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006160 https://doaj.org/article/ebb7e2223ed14d3b805b46d2c9ede416 |
op_doi |
https://doi.org/10.1371/journal.pntd.0006160 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
12 |
container_issue |
1 |
container_start_page |
e0006160 |
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1766341524656750592 |