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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA067760-04
Application #
6269710
Study Section
Project Start
1998-09-30
Project End
1999-09-29
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Nishioka, David; Marcell, Vanessa; Cunningham, Meghan et al. (2003) The use of early sea urchin embryos in anticancer drug testing. Methods Mol Med 85:265-76
Kerwin, Sean M; Chen, Grace; Kern, Jonathan T et al. (2002) Perylene diimide G-quadruplex DNA binding selectivity is mediated by ligand aggregation. Bioorg Med Chem Lett 12:447-50
Kern, Jonathan T; Kerwin, Sean M (2002) The aggregation and G-quadruplex DNA selectivity of charged 3,4,9,10-perylenetetracarboxylic acid diimides. Bioorg Med Chem Lett 12:3395-8
Kern, Jonathan T; Thomas, Pei Wang; Kerwin, Sean M (2002) The relationship between ligand aggregation and G-quadruplex DNA selectivity in a series of 3,4,9,10-perylenetetracarboxylic acid diimides. Biochemistry 41:11379-89
Sun, Daekyu (2002) Biotinylated primer for detecting telomerase activity without amplification. Methods Mol Biol 191:165-71
Shi, D F; Wheelhouse, R T; Sun, D et al. (2001) Quadruplex-interactive agents as telomerase inhibitors: synthesis of porphyrins and structure-activity relationship for the inhibition of telomerase. J Med Chem 44:4509-23
Duan, W; Rangan, A; Vankayalapati, H et al. (2001) Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects. Mol Cancer Ther 1:103-20
Sun, D; Hurley, L H (2001) Targeting telomeres and telomerase. Methods Enzymol 340:573-92
Izbicka, E; Barnes, L D; Robinson, A K et al. (2001) Alterations in DNA repair and telomere maintenance mechanism affect response to porphyrins in yeast. Anticancer Res 21:1899-903
Han, H; Langley, D R; Rangan, A et al. (2001) Selective interactions of cationic porphyrins with G-quadruplex structures. J Am Chem Soc 123:8902-13

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