The therapeutic potential of inhibitors of the trypanothione cycle.
There is an urgent need for new drugs in the treatment of human African trypanosomiasis, Chagas' disease and leishmaniasis. This article provides an overview of current drugs, formulations and their deficiencies. Targets for the design of new drugs and the rational provided for targeting enzymes of the trypanothione cycle are described. Biochemical aspects of the cycle and the currently investigated target trypanothione reductase are discussed as are the several classes of inhibitors and their in vitro potencies. Evidence is provided for considering the tryparedoxins as a new target for antiprotozoal chemotherapy and a summary of glutathione-based inhibitors with significant in vitro activity is reported.
D'Silva
Claudius
C
Department of Chemistry & Materials, The Manchester Metropolitan University, John Dalton Building, Chester Street, Manchester M1 5GD, UK.
Daunes
Sylvie
S
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D006801:Humans; D007896:Leishmaniasis / Q000188:drug therapy; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors; D013095:Spermidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014344:Trypanocidal Agents / Q000737:chemistry / Q000627:therapeutic use*; D014353:Trypanosomiasis, African / Q000188:drug therapy
D004791:Enzyme Inhibitors; D018000:Receptors, Peptide; D014344:Trypanocidal Agents; C035560:glutathione receptor; C114110:tryparedoxin; D013879:Thioredoxins; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D013095:Spermidine