The long term objective of this project is the design of new drugs to treat human diseases caused by parasitic trypanosomatids. The research proposed involves the purification and characterization of the enzymes which control the synthesis and metabolism of the trypanosomatiol metabolite N1, N8 - bis(glutathionyl) spermidine (trypanothione). The structure and catalytic mechanism of the enzymes trypanothione reductase and trypanothione synthetase will be studied and compounds which inhibit these enzymes will be chemically synthesized. These compounds will be tested in vitro and in vivo for trypanocidal activity against Trypanosoma brucei T. cruzi and various Leishmania spp. which are major causes of human and animal disease in the developing world. At present, few drugs are available to treat parasitic infections and in general therapeutic index of these compounds is low. To avoid host toxicity, new trypanocidal drugs should be directed against metabolic processes unique to the parasite. The trypanosomatid metabolite, trypanothione, and the enzymes which control the synthesis and metabolic actions of this compound are present in all kinetoplastid species but this system is not known in mammalian cells. Consequently, this aspect of parasite biochemistry represents an important new area for pharmacological intervention.
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| Kuriyan, J; Kong, X P; Krishna, T S et al. (1991) X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution. Proc Natl Acad Sci U S A 88:8764-8 |
| Kuriyan, J; Wong, L; Guenther, B D et al. (1990) Preliminary crystallographic analysis of trypanothione reductase from Crithidia fasciculata. J Mol Biol 215:335-7 |
| Henderson, G B; Yamaguchi, M; Novoa, L et al. (1990) Biosynthesis of the trypanosomatid metabolite trypanothione: purification and characterization of trypanothione synthetase from Crithidia fasciculata. Biochemistry 29:3924-9 |
| Fairlamb, A H; Henderson, G B; Cerami, A (1989) Trypanothione is the primary target for arsenical drugs against African trypanosomes. Proc Natl Acad Sci U S A 86:2607-11 |
