The trypanothione system and the opportunities it offers to create drugs for the neglected kinetoplast diseases

Parasitic trypanosomatids (Kinetoplastida) are the causative agents of devastating and hard-to-treat diseases such as African sleeping sickness, Chagas disease and various forms of Leishmaniasis. Altogether they affect > 30 Million patients, account for half a million fatalities p.a. and cause substantial economical problems in the Third World due to human morbidity and life stock losses. The design of efficacious and safe drugs is expected from inhibition of metabolic pathways that are unique and essential to the parasite and absent in the host. In this respect, the trypanothione system first detected in the insect-pathogenic trypanosomatid Crithidia fasciculata qualified as an attractive drug target area. The existence of the system in pathogenic relatives was established by homology cloning and PCR. The vital importance of the system was verified in Trypanosoma brucei by dsRNA technology or knock-out in other trypanosomatids, respectively, and is explained by its pivotal role in the parasite's antioxidant defense and DNA synthesis. The key system component is the bis-glutathionyl derivative of spermidine, trypanothione. It is the proximal reductant of tryparedoxin which substitutes for thioredoxin-, glutaredoxin- and glutathione-dependent reactions. Heterologous expression, functional characterization and crystallization of recombinant system components finally enable structure-based rational inhibitor design.