Research

Nucleic Acid Triggered Prodrug and Probe Activation. We have proposed a completely new approach to disease-specific anticancer and antiviral diagnostic and therapeutic agents that is based on the ease by which specific nucleic acid sequences can be recognized by simple Watson Crick base pairing rules.

The idea is to attach a cytotoxic drug to an oligodeoxynucleotide (ODN) or analog such as PNA that recognizes one half of a nucleic acid sequence that is unique to a cancer or virus, and a catalyst to another ODN or analog that recognizes the other half of the sequence. Only in the cancer or virally infected cells will the two components be brought together by the disease specific nucleic acid and cause the catalytic release of the cytotoxic agent which then kills the diseased cell. We have recently validated this approach with an in vitro PNA-based model system in which RNA triggers the release of hydroxycoumarin, and are now developing systems that will work in breast, cervical, and prostate cancer cells.

Sunlight and Skin Cancer. Though many of the carcinogenic effects of sunlight can be attributed to DNA photoproducts, such as the cis-syn dimer, the biological activities of individual photoproducts are largely unknown.

To determine the precise structure-activity relationships, we have developed building blocks for the site-specific incorporation of DNA photoproducts into ODNs by automated synthesis. We are currently most interested in understanding how polymerases are able to bypass DNA photoproducts and the molecular basis of the mutations that are created in the process. To this end, we have been studying the structure and properties of photodamaged DNA by 2D NMR and X-ray crystallography, and the bypass mechanism of photodamaged DNA with DNA polymerases by steady state and pre-steady state kinetics, fluorescence depolarization measurements, mass spectrometry, site-directed mutagenesis, and DNA array technology.

Design and Synthesis of Anti-Sense and Anti-Gene Anti-Cancer Agents. Our most recent area of research involves the design and synthesis of LNAs, PNAs, and polyamides targeted to genes and mRNAs for the purpose of detecting and/or selectively killing cancer cells through the action of appended probes and reagents. In one project, we are collaborating with Dr. Welch and Dr. Wooley's groups to help construct nanoparticles adorned with the PET imaging agent ⁶⁴Cu and cancer cell specific PNAs. In another, we are trying to shut down heat shock protein to enhance the effects of ionizing radiation in collaboration with Dr. Roti Roti's laboratory in Cancer Biology.

Selected Publications

• Z. Ma and J.S. Taylor, "PNA-Based RNA-Triggered Drug-Releasing System," Bioconjug Chem, 14, 679 (2003).
• L. Sun, K. Zhang, L. Zhou, P. Hohler, E.T. Kool, F. Yuan, Z. Wang, and J.S. Taylor, "Yeast Pol eta Holds a Cis-Syn Thymine Dimer Loosely in the Active Site during Elongation Opposite the 3'-T of the Dimer, but Tightly Opposite the 5'-T," Biochemistry, 42, 9431 (2003).
• X. Li and J.S. Taylor, "General strategy for the preparation of membrane permeable fluorogenic peptide ester conjugates for in vivo studies of ester prodrug stability," ioorg Med Chem, 12, 545 (2004).