Title:Trypanothione Reductase and Superoxide Dismutase as Current Drug Targets for Trypanosoma cruzi: An Overview of Compounds with Activity against Chagas Disease
Volume: 24
Issue: 11
Author(s): Ivan Beltran-Hortelano, Silvia Perez-Silanes*Silvia Galiano
Affiliation:
- Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Campus Universitario, 31008, Pamplona,Spain
Keywords:
Chagas disease, Trypanosoma cruzi, trypanothione reductase, superoxide dismutase, trypanocidal activity,
drug targets, drug development, structure-activity relationship.
Abstract: It has been over a century since Carlos Chagas discovered the Trypanosoma cruzi
(T. cruzi) as the causative agent of Chagas disease (CD), a neglected tropical disease with
several socioeconomic, epidemiological and human health repercussions. Currently, there are
only two commercialized drugs to treat CD in acute phase, nifurtimox and benznidazol, with
several adverse side effects. Thus, new orally available and safe drugs for this parasitic infection
are urgently required. One strategy of great importance in new drug discovery programmes
is based on the search of molecules enabling to interfere with enzymes involved in
T. cruzi metabolism. This review will focus on two of the most promising targets for the therapy
of CD: trypanothione reductase (TR) and the iron-containing superoxide dismutase (Fe-
SOD), which protect the parasite against oxidative damage by reactive oxygen species. A
brief comparison of the function, mechanism of action and the active sites between T. cruzi
TR and Fe-SOD with their analogues enzymes in human, glutathione reductase (GR) and the
corresponding SODs, will be discussed. This review will also summarize the recent development
and structure-activity relationships of novel compounds reported for their ability to selectively
inhibit these targets, aiming to define molecular bases in the search for new effective
treatment of CD.
