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Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs

    Gianni Colotti

    * Author for correspondence

    National Research Council of Italy, Institute of Molecular Biology & Pathology, Rome, Italy c/o Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy.

    ,
    Paola Baiocco

    Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    ,
    Annarita Fiorillo

    Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    ,
    Alberto Boffi

    Istituto Pasteur Fondazione Cenci-Bolognetti c/o Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    ,
    Elena Poser

    Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    ,
    Francesco Di Chiaro

    Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    &
    Andrea Ilari

    National Research Council of Italy, Institute of Molecular Biology & Pathology, Rome, Italy c/o Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    Istituto Pasteur Fondazione Cenci-Bolognetti c/o Department of Biochemical Sciences ‘A. Rossi Fanelli‘, University Sapienza, Rome, Italy

    Published Online:https://doi.org/10.4155/fmc.13.146

    Leishmaniasis is a neglected disease that kills 60,000 people worldwide, and which is caused by the protozoa Leishmania. The enzymes of the trypanothione pathway: trypanothione synthetase-amidase, trypanothione reductase (TR) and tryparedoxin-dependent peroxidase are absent in human hosts, and are essential for parasite survival and druggable. The most promising target is trypanothione synthetase-amidase, which has been also chemically validated. However, the structural data presented in this review show that TR also should be considered as a good target. Indeed, it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents. Moreover, TR trypanothione-binding site is not featureless but contains a sub-pocket where inhibitors bind, potentially useful for the design of new lead compounds.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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