title: Thiol redox biology of trypanosomatids and potential targets for chemotherapy.
abstract: Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different forms of leishmaniasis. This family of protozoan parasite possesses a trypanothione-based redox metabolism that provides the reducing equivalents for various vital processes such as the biosynthesis of DNA precursors and the detoxification of hydroperoxides. Almost all enzymes of the redox pathway proved to be essential and therefore fulfil one crucial prerequisite for a putative drug target. Trypanothione synthetase and trypanothione reductase are present in all trypanosomatids but absent from the mammalian host which, in addition to the essentiality, renders them highly specific. The chemotherapy research on both enzymes is further supported by the availability of high-throughput screening techniques and crystal structures. In this review we focus on the recent advances and limitations in the development of lead compounds targeting trypanothione synthetase and trypanothione reductase. We present an overview of the available inhibitors and discuss future perspectives including other components of the parasite-specific redox pathway.
authors.affiliation: Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Electronic address: alejandro.leroux@bzh.uni-heidelberg.de.
authors.forename: Alejandro E
authors.initials: AE
authors.lastname: Leroux
authors.affiliation: Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Electronic address: luise.krauth-siegel@bzh.uni-heidelberg.de.
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
mesh_terms: D019732:Amide Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D007891:Leishmania / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D007896:Leishmaniasis / Q000188:drug therapy / Q000469:parasitology; D058990:Molecular Targeted Therapy; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D013438:Sulfhydryl Compounds; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D019732:Amide Synthases; C064407:trypanothione synthetase
keywords: Drug; Inhibitor; Leishmania; Trypanosoma; Trypanothione reductase; Trypanothione synthetase