Leishmaniasis, Chagas disease, and sleeping sickness affect millions of people worldwide and lead to the death of about 50 000 humans per year. These diseases are caused by the kinetoplastids Leishmania, Trypanosoma cruzi, and Trypanosoma brucei, respectively. These parasites share many general features, including gene conservation, high amino acid identity among proteins, the presence of subcellular structures as glycosomes and the kinetoplastid, and genome architecture, that may make drug development family specific, rather than species-specific, i.e., on the basis of the inhibition of a common, conserved parasite target. However, no optimal molecular targets or broad-spectrum drugs have been identified to date to cure these diseases. Here, the LeishBox from GlaxoSmithKline high-throughput screening, a 192-molecule set of best antileishmanial compounds, based on 1.8 million compounds, was used to identify specific inhibitors of a validated Leishmania target, trypanothione reductase (TR), while analyzing in parallel the homologous human enzyme glutathione reductase (GR). We identified three specific highly potent TR inhibitors and performed docking on the TR solved structure, thereby elucidating the putative molecular basis of TR inhibition. Since TRs from kinetoplastids are well conserved, and these compounds inhibit the growth of Leishmania, Trypanosoma cruzi, and Trypanosoma brucei, the identification of a common validated target may lead to the development of potent antikinetoplastid drugs.

Toward a Drug Against All Kinetoplastids: From LeishBox to Specific and Potent Trypanothione Reductase Inhibitors / Ilari, Andrea; Genovese, Ilaria; Fabiana, Fiorillo; Battista, Theo; Ilenia De Ionna, ; Fiorillo, Annarita; Colotti, Gianni. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 15:8(2018), pp. 3069-3078. [10.1021/acs.molpharmaceut.8b00185]

Toward a Drug Against All Kinetoplastids: From LeishBox to Specific and Potent Trypanothione Reductase Inhibitors

Andrea Ilari;Ilaria Genovese;BATTISTA, THEO;Annarita Fiorillo;Gianni Colotti
2018

Abstract

Leishmaniasis, Chagas disease, and sleeping sickness affect millions of people worldwide and lead to the death of about 50 000 humans per year. These diseases are caused by the kinetoplastids Leishmania, Trypanosoma cruzi, and Trypanosoma brucei, respectively. These parasites share many general features, including gene conservation, high amino acid identity among proteins, the presence of subcellular structures as glycosomes and the kinetoplastid, and genome architecture, that may make drug development family specific, rather than species-specific, i.e., on the basis of the inhibition of a common, conserved parasite target. However, no optimal molecular targets or broad-spectrum drugs have been identified to date to cure these diseases. Here, the LeishBox from GlaxoSmithKline high-throughput screening, a 192-molecule set of best antileishmanial compounds, based on 1.8 million compounds, was used to identify specific inhibitors of a validated Leishmania target, trypanothione reductase (TR), while analyzing in parallel the homologous human enzyme glutathione reductase (GR). We identified three specific highly potent TR inhibitors and performed docking on the TR solved structure, thereby elucidating the putative molecular basis of TR inhibition. Since TRs from kinetoplastids are well conserved, and these compounds inhibit the growth of Leishmania, Trypanosoma cruzi, and Trypanosoma brucei, the identification of a common validated target may lead to the development of potent antikinetoplastid drugs.
2018
inhibitors; LeishBOX; Leishmania; neglected diseases; Trypanosoma; trypanothione reductase; Molecular Medicine; 3003; Drug Discovery3003 Pharmaceutical Science
01 Pubblicazione su rivista::01a Articolo in rivista
Toward a Drug Against All Kinetoplastids: From LeishBox to Specific and Potent Trypanothione Reductase Inhibitors / Ilari, Andrea; Genovese, Ilaria; Fabiana, Fiorillo; Battista, Theo; Ilenia De Ionna, ; Fiorillo, Annarita; Colotti, Gianni. - In: MOLECULAR PHARMACEUTICS. - ISSN 1543-8384. - 15:8(2018), pp. 3069-3078. [10.1021/acs.molpharmaceut.8b00185]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1175786
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