Nucleic Acid Triggered Prodrug and Probe Activation Systems We have been working on a completely new approach to disease-specific anticancer and antiviral imaging 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. (See: Ma & Taylor, Proc. Natl. Acad. Sci. 2000 97, 11159. ) The idea is to attach a prodrug or fluorogenic probe to an ODN or analog 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 and/or probe which enables the cell to be imaged.

We originally validated the NATPA approach in vitro with a model system based on p-nitrophenyl ester hydrolysis. This system showed catalytic turnover, but was not very efficient. The other problem was that the nitrophenyl ester was too labile, and is prone to spontaneous hydrolysis at pH 7.

Our main focus has been on understanding the mechanism of C to T and CC to TT mutations, and have been focusing on understanding the structure-activity relationships in deamination of C within cis-syn cyclobutane dimers and have recently completed a study of the sequence dependence of deamination. Currently, we are investigating the effect of protein binding and nucleosome structure on deamination.