Trypanosomes & Drug Design
Groupleader: Luise Krauth-Siegel
Trypanosomes and leishmania, the causative agents of African sleeping sickness (Trypanosoma brucei), South American Chagas' disease (T. cruzi) and the different forms of leishmaniasis, have an unprecedented thiol redox metabolism. All of these parasitic protozoa lack glutathione reductase and thioredoxin reductases. The main non-protein thiols are glutathionylspermidine conjugates such as trypanothione [bis(glutathionyl)spermidine] which are kept reduced by the essential flavoenzyme trypanothione reductase.
Our work focuses on irreversible inhibitors and subversive substrates of trypanothione reductase as potential drug candidates. A second approach deals with the detoxification of hydroperoxides. African trypanosomes have 2-Cys-peroxiredoxins and glutathione peroxidase-type enzymes which both obtain their reducing equivalents from the unique cascade composed of trypanothione reductase, trypanothione and tryparedoxin. Site directed mutagenesis and the recent structural analysis revealed that the catalytic mechanism of the parasite glutathione peroxidase-type enzyme differs totally from that of the homologous mammalian selenoenzymes. The role of mono- and dithiol glutaredoxins in the redox metabolism of African trypanosomes is the third current focus.
Aim of our work is to elucidate the unique trypanothione metabolism of trypanosomatids and to contribute to the rational development of new antiparasitic drugs on the basis of specific enzyme inhibitors.
Download BZH Report Krauth-Siegel 2011-2013