Abstract
ABSTRACTAfrican trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens.
Highlights
African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei
The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals
To investigate ribonucleotide reductase (RNR) inhibition as a potential therapeutic target for human African trypanosomiasis (HAT), we first identified two RNR enzyme subunits in the T. brucei genome resource TritrypDB [26]—TbRNR1 and TbRNR2
Summary
African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo These results support drug discovery efforts targeting the cell cycle, for African trypanosomiasis but possibly for other infections by eukaryotic pathogens. Nifurtimox-eflornithine combination therapy (NECT) has proven very successful against later-stage infection [12], and there is ongoing development of drugs targeting sterols, histone deacetylation, and proteasomes [9, 13,14,15] These treatments exploit unique or vulnerable aspects of trypanosome biology, and further study will ideally yield highly selective agents with minimal host toxicity. This has led some to explore drug repurposing— utilizing existing drugs with proven safety profiles and preexisting clinical experience—for the treatment of other diseases [16]
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