The overall objective of the University of Texas at Austin component of the NCDDG will be to design and synthesize specific inhibitors of human telomerases. The recognition that telomerases are critical in maintaining the integrity of the ends of chromosomes, thus preventing chromosomal abnormalities and, ultimately, cell death, has led to the proposal that they might be attractive targets for selective action of antitumor agents. The selective effect of inhibitors of telomerases is envisaged to arise from the active role of these enzymes in rapidly proliferating cells (i.e., cancer cells) vs. their absence from normal cells. The specific objectives of the proposed research carried out by the Austin group are to: l. Structurally characterize by high-field NMR unique nucleic acid components of the telomerase reaction, namely: the telomerase RNA-DNA duplex, the DNA hairpin, and DNA tetraplex corresponding to the human 5'- TTAGGG repeat region generated by telomerase activity. 2. Use computer molecular modeling to design drugs that will bind specifically to the hairpin stem structure and the RNA-DNA duplex region generated by telomerase activity. 3. Trap translocation intermediates using nucleoside analogs or nucleic acid-binding drugs and investigate their structure using chemical footprinting techniques. 4. Design and synthesize small molecular weight molecules that target unique features of telomerase translocation intermediates. Successful completion of the project will require expertise from structural biology (high-field NMR and molecular modeling) biochemistry (DNA footprinting, polymerase assays, drug-DNA interactions), and medicinal chemistry (computational chemistry, synthesis, inhibitor design). Leads generated in this study will be integrated into other components of the NCDDG.
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