Parasite-specific trypanothione reductase as a drug target molecule

Parasitol Res. 2003 Jun;90 Suppl 2:S77-85. doi: 10.1007/s00436-002-0771-8. Epub 2003 Apr 23.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antiparasitic Agents / chemistry
  • Antiparasitic Agents / pharmacology*
  • Binding Sites
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • NADH, NADPH Oxidoreductases / chemistry
  • Peptides / pharmacology
  • Polyamines / pharmacology
  • Species Specificity
  • Sulfhydryl Compounds / metabolism
  • Trypanosoma / drug effects
  • Trypanosoma / enzymology*

Substances

  • Antiparasitic Agents
  • Enzyme Inhibitors
  • Peptides
  • Polyamines
  • Sulfhydryl Compounds
  • NADH, NADPH Oxidoreductases
  • trypanothione reductase