title: Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gianni
authors.initials: G
authors.lastname: Colotti
authors.forename: Paola
authors.initials: P
authors.lastname: Baiocco
authors.forename: Annarita
authors.initials: A
authors.lastname: Fiorillo
authors.forename: Alberto
authors.initials: A
authors.lastname: Boffi
authors.forename: Elena
authors.initials: E
authors.lastname: Poser
authors.forename: Francesco Di
authors.initials: FD
authors.lastname: Chiaro
authors.forename: Andrea
authors.initials: A
authors.lastname: Ilari
mesh_terms: D019732:Amide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006046:Gold / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007891:Leishmania / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012834:Silver / Q000737:chemistry / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D012834:Silver; D006046:Gold; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D019732:Amide Synthases; C064407:trypanothione synthetase; D005978:Glutathione; D013095:Spermidine