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Study of novel enzymic targets for the develpment of drugs against pathogenic agents responsible of poverty related diseases

 

Federico Focher

 

Entamoeba histolytica is an intestinal parasite and the causative agent of amoebiasis, which is a significant source of morbididy and mortality in developing countries. Antiamoebic drugs are metronidazole, the major drug of choice, and other nitroimidazole derivatives such as diloxanide furoate, emetine and chloroquine. Since the potential for development of drug resistance is always present and vaccine development appears to be a distant goal, we searched for novel possible targets for anti-Entamoeba chemotherapy. Since E. histolytica bases its supply of nucleotides only on the salvage pathway, we were confident that enzymes involved in the salvage pathway of nucleotides could represent possible targets to control parasite proliferation. Based upon the genome sequence now available, we cloned, expressed and purified thymidine kinase (Eh-TK) and uridine-cytidine kinase (Eh-UCK) from E. histolytica.
In order to find alternative treatments of E. histolytica infection we tested several nucleoside analogs, both in vitro, against Eh-TK and Eh-UCK, and in cell culture. Our results indicate that the inhibitors or alternative substrates we tested against both enzymes, althought partially cytostatic, are poorly cytotoxic against E. histolytica.



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