This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The importance of eukaryotic pathogens for human disease is enormous. For example, more than 60,000 people will die this year from sleeping sickness caused by the protozoans Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. Only a single new anti-trypanosome drug has been developed in the past 50 years. This drug, difluormethylornithine (DFMO), is effective only against T.b. gambiense, and it has been difficult and costly to synthesize.
We aim to develop novel RNA therapeutics to prevent the interaction of the hinge-region of U3 small nucleolar RNA (snoRNA) and the ETS (External Transcribed Spacer) of the ribosomal RNA precursor, thus preventing ribosome biogenesis in the eukaryotic pathogen. As a proof of principle and the foundation for future drug design, we will confirm whether oligonucleotides targeted against the U3 snoRNA hinge-region of Trypanosoma brucei block ribosome formation and growth without affecting cultured human cells. Resistance against the prevention of U3 hinge-ETS base-pairing would be less likely than resistance developed in response to single point mutations.
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