: We propose to develop a new and general approach to the design and synthesis of easily programmable, disease-specific chemotherapeutic agents and probes that make direct use of genetic information to trigger the death of a diseased cell. The idea is to make use of a disease-specific mRNA or DNA sequence to direct the association of a prodrug and an activator capable of converting the prodrug to an active drug. In this approach the nucleic acid is used not as a target, but as a trigger, and thus does not depend on the biological activity of the disease-specific nucleic acid sequence, only on its uniqueness and accessibility. We propose to investigate the feasibility of one formulation of this new concept to chemotherapy in which the prodrug component consists of a drug attached to a segment of PNA that is complementary to one section of a disease specific mRNA, and the activating component consists of a catalyst attached to a segment of PNA that is complementary to the adjoining section of the mRNA. Only in a diseased cell can the disease specific mRNA cause the two components to associate which then results in the conversion of the prodrug to a cytotoxic drug and death of the cell. We envision that indiscriminant delivery of the prodrug and activating components into cells will be effected by fusing the two components to the TAT protein transduction domain. This project will be aimed at developing and validating: (1) bio-compatible stoichiometric and catalytic prodrug activation systems, (2) PNA-based systems for directing the assembly of prodrug and activation components on HIV and prostate cancer-specific mRNA in vitro, (3) TAT protein transduction domain systems for delivery of PNAS into HIV and prostate cancer cells, and (4) nucleic acid triggered prodrug activation in HIV and PSA expressing prostate cancer cells. Part of this project also involves the use of the prodrug activation systems to release fluorescent probes for monitoring prodrug activation reactions in vitro and in vivo, and thus may also have practical applications as in vitro or in vivo diagnostic agents.
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| Cai, Jianfeng; Li, Xiaoxu; Taylor, John Stephen (2005) Improved nucleic acid triggered probe activation through the use of a 5-thiomethyluracil peptide nucleic acid building block. Org Lett 7:751-4 |
| Cai, Jianfeng; Li, Xiaoxu; Yue, Xuan et al. (2004) Nucleic acid-triggered fluorescent probe activation by the Staudinger reaction. J Am Chem Soc 126:16324-5 |
| Li, Xiaoxu; Taylor, John Stephen (2004) General strategy for the preparation of membrane permeable fluorogenic peptide ester conjugates for in vivo studies of ester prodrug stability. Bioorg Med Chem 12:545-52 |
| Ma, Zhaochun; Taylor, John-Stephen (2003) PNA-based RNA-triggered drug-releasing system. Bioconjug Chem 14:679-83 |
