Parasite-specific trypanothione reductase as a drug target molecule.
Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different manifestations of leishmaniasis. New drugs against these parasitic protozoa are urgently needed since the current drugs are unsatisfactory, in particular due to serious adverse side effects. In trypanosomes and leishmanias, the nearly ubiquitous glutathione/glutathione reductase system is replaced by trypanothione and trypanothione reductase. The essential role of trypanothione reductase in the parasite thiol metabolism and its absence from the mammalian host render the enzyme a highly attractive target molecule for a structure-based drug development against trypanosomatids. This article provides an overview on the known classes of trypanothione reductase inhibitors and their in vitro activity against parasitic protozoa. The (dis)advantages of the different types of compounds as potential drug candidates as well as modern computer-based approaches to the identification of new leads are discussed.
Krauth-Siegel
R Luise
RL
Biochemie-Zentrum Heidelberg, Universität Heidelberg, Im Neuenheimer Feld 504, 69120 Heidelberg, Germany. krauth-siegel@urz.uni-heidelberg.de
Inhoff
Oliver
O
D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010455:Peptides / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology*
D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D011073:Polyamines; D013438:Sulfhydryl Compounds; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase