title: Trypanothione Reductase and Superoxide Dismutase as Current Drug Targets for Trypanosoma cruzi: An Overview of Compounds with Activity against Chagas Disease.
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.
authors.affiliation: Universidad de Navarra, Instituto de Salud Tropical (ISTUN), Campus Universitario, 31008, Pamplona. Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Beltran-Hortelano
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Campus Universitario, 31008, Pamplona. Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Perez-Silanes
authors.affiliation: Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Química Orgánica y Farmacéutica, Campus Universitario, 31008, Pamplona. Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Galiano
mesh_terms: D020134:Catalytic Domain; D014355:Chagas Disease / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010640:Phenothiazines / Q000737:chemistry; D011073:Polyamines / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D010640:Phenothiazines; D011073:Polyamines; D014344:Trypanocidal Agents; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase
keywords: Chagas disease; Trypanosoma cruzi; drug development; drug targets; structure-activity relationship; superoxide dismutase; trypanocidal activity; trypanothione reductase