Expression, Purification, Characterization, and in Vivo Targeting of Trypanosome CTP Synthetase for Treatment of African Sleeping Sickness
| Autor: | Artur Fijolek, Anders Hofer, Lars Thelander |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Trypanosoma brucei gambiense viruses Trypanosoma brucei brucei Cytidine Biochemistry Cytosine Mice In vivo Animals Humans Carbon-Nitrogen Ligases heterocyclic compounds Enzyme Inhibitors CTP synthetase Molecular Biology Dose-Response Relationship Drug biology Cell Biology Trypanocidal Agents Mice Inbred C57BL Kinetics enzymes and coenzymes (carbohydrates) Trypanosomiasis African biology.protein |
| Zdroj: | Journal of Biological Chemistry. 282:11858-11865 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m611580200 |
| Popis: | African sleeping sickness is a fatal disease caused by two parasite subspecies: Trypanosoma brucei gambiense and T. b. rhodesiense. We previously reported that trypanosomes have extraordinary low CTP pools compared with mammalian cells. Trypanosomes also lack salvage of cytidine/cytosine making the parasite CTP synthetase a potential target for treatment of the disease. In this study, we have expressed and purified recombinant T. brucei CTP synthetase. The enzyme has a higher K(m) value for UTP than the mammalian CTP synthetase, which in combination with a lower UTP pool may account for the low CTP pool in trypanosomes. The activity of the trypanosome CTP synthetase is irreversibly inhibited by the glutamine analogue acivicin, a drug extensively tested as an antitumor agent. There is a rapid uptake of acivicin in mice both given intraperitoneally and orally by gavage. Daily injection of acivicin in trypanosome-infected mice suppressed the infection up to one month without any significant loss of weight. Experiments with cultured bloodstream T. brucei showed that acivicin is trypanocidal if present at 1 mum concentration for at least 4 days. Therefore, acivicin may qualify as a drug with "desirable" properties, i.e. cure within 7 days, according to the current Target Product Profiles of WHO and DNDi. |
| Databáze: | OpenAIRE |
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