Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents.
Trypanothione is the key molecule in the defence mechanism of Trypanosoma and Leishmania against oxidative stress. The uniqueness of trypanothione makes the metabolism of this molecule an attractive target in antitrypanosomal and antileishmanial drug design. It became clear that this antioxidant cascade can be considered as the "Achilles heel" of these parasites. The following targets and their respective inhibitors will be discussed: biosynthesis of trypanothione with glutathionylspermidine synthetase and trypanothione synthetase; biosynthesis of glutathione with gamma-glutamylcysteine synthetase; biosynthesis of spermidine with ornithine decarboxylase; trypanothione hydroperoxide metabolism with tryparedoxine peroxidase, tryparedoxine and trypanothione reductase.
Augustyns
K
K
Department of Medicinal Chemistry, University of Antwerp (UIA), Universiteitsplein, Los Antwerpen, B-2610, Belgium. Koen.Augustyns@uia.ua.ac.be
Amssoms
K
K
Yamani
A
A
Rajan
P K
PK
Haemers
A
A
D000818:Animals; D015195:Drug Design; D005978:Glutathione / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013095:Spermidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism; D014352:Trypanosomiasis / Q000188:drug therapy* / Q000378:metabolism
D014344:Trypanocidal Agents; C044809:trypanothione; D005978:Glutathione; D013095:Spermidine