alpha-Difluoromethylornithine (RMI 71,782), a specific irreversible inhibitor of the first step in polyamine biosynthesis, that is, the formation of putrescine from ornithine by ornithine decarboxylase, cures mice infected with a virulent, rodent-passaged strain of Trypanosoma brucei brucei. This parasite is closely related to the trypanosomes that cause human sleeping sickness. The drug, which is remarkably nontoxic, was effective when administered in drinking water or by intubation. The ability of the compound to inhibit ornithine decarboxylase in vitro was demonstrated by the reduced amounts of putrescine synthesized from tritiated ornithine in Trypanosoma brucei suspensions. These observations direct attention to polyamine metabolism as a target for chemotherapy of parasitic diseases.
Polyamines are essential cell constituents for all organisms. The present review highlights important differences in the synthesis, degradation, and interconversion of polyamines between the protozoan parasites (Trypanosoma brucei, Trypanosoma cruzi, Cryptosporidium parvum and Trichomonas vaginalis) and their mammalian hosts. Approaches include development of mono- and di-substituted polyamine analogs targeting polyamine interconversion, as well as more traditional targeting of synthetic enzymes and related pathways.
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