Enzymes of the Trypanothione Metabolism as Targets for Antitrypanosomal Drug Development

Title: Enzymes of the Trypanothione Metabolism as Targets for Antitrypanosomal Drug Development

Volume: 2 Issue: 11

Author(s): Armin Schmidt and R. Luise Krauth-Siegel

Affiliation:

Keywords: antitrypanosomal drug development, trypanothione metabolism, biosynthesis of trypanothione

Abstract: Trypanosomatids are the causative agents of African sleeping sickness, Chagas disease and the three forms of leihmaniasis. New drugs against these parasitic protozoa are urgently needed since the currently available chemotherapy is not at all satisfying. One promising approach towards the development of new drugs is based on the design of specific enzyme inhibitors. Trypanosomes and leishmania possess a unique thiol metabolism in which the ubiquitous glutathione / glutathione reductase system is replaced by trypanothione and trypanothione reductase. The dithiol trypanothione is the key molecule for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides, and the sequestration / export of thiol conjugates. Synthesis and reduction of trypanothione are essential for the maintenance of a reducing intracellular milieu which renders the respective enzymes attractive drug target molecules. Here we present the current state of knowledge of the thiol metabolism of trypanosomatids, comprising the trypanothione / tryparedoxin, thioredoxin, and ovothiol systems of the parasites. The most effective inhibitors of the enzymes known to date, their mode of action, and the (dis)advantages of different types of inhibitors as potential drug candidates will be discussed.

Cite this article as:

Schmidt Armin and Krauth-Siegel Luise R., Enzymes of the Trypanothione Metabolism as Targets for Antitrypanosomal Drug Development, Current Topics in Medicinal Chemistry 2002; 2 (11) . https://dx.doi.org/10.2174/1568026023393048