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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 (IC 50 ) of 150 ± 15  μ M for 1  μ M 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 IC 50  values within the same range. All three hits affected the viability of the extra-cellular form of  L. infantum  parasites with IC 50  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 IC 50  values lower than 4.2  μ M. Selected compounds exhibited selectivity indexes between 19 to 38, which reflects their potential as promising anti- Leishmania  molecules.

plos neglected tropical diseases

Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A