Abstract
Approximately ten million people suffer from Chagas disease worldwide, caused by Trypanosoma cruzi, with the disease burden predominately focused in Latin America. Sleeping sickness is another serious health problem, caused by Trypanosoma brucei, especially in sub-Saharan countries. Unfortunately, the drugs currently available to treat these diseases have toxic effects and are not effective against all disease phases or parasite strains. Therefore, there is a clear need for the development of novel drugs and drug targets to treat these diseases. We propose the trypanosome prereplication machinery component, Orc1/Cdc6, as a potential target for drug development. In trypanosomes, Orc1/Cdc6 is involved in nuclear DNA replication, and, despite its involvement in such a conserved process, Orc1/Cdc6 is distinct from mammalian Orc1 and Cdc6 proteins. Moreover, RNAi-mediated silencing of trypanosome Orc1/Cdc6 expression in T. brucei decreased cell survival, indicating that Orc1/Cdc6 is critical for trypanosome survival.
Highlights
Approximately ten million people have Chagas disease worldwide, with the disease burden being centered in Latin America
In spite of the conserved nature of essential pathways among eukaryotic organisms, we identified a trypanosome prereplication machinery component that is fundamental for replication and that is distinct from eukaryotic prereplication machinery; this component is necessary for origin selection and the establishment of the DNA replication fork [24]
DNA replication in eukaryotes begins with the assembly of the prereplication complex on regions along chromosomes known as replication origins [25, 26]
Summary
Approximately ten million people have Chagas disease worldwide, with the disease burden being centered in Latin America. Drugs used to treat Chagas disease and sleeping sickness have undesired toxic side effects and are not effective against all parasite life cycle stages or parasite strains because of drug resistance. The need for new drugs and novel drug targets to treat both Chagas disease and sleeping sickness is evident These drugs should target fundamental pathways within these parasites. In spite of the conserved nature of essential pathways among eukaryotic organisms, we identified a trypanosome prereplication machinery component that is fundamental for replication and that is distinct from eukaryotic prereplication machinery; this component is necessary for origin selection and the establishment of the DNA replication fork [24] These data indicate that this enzyme is a potential drug target for the treatment of both Chagas disease and sleeping sickness
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