NUCLEIC ACID TRIGGERED DRUG & PROBE RELEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该项目的目的是开发一种新的通用方法来设计和合成易于编程的疾病特异性化疗药物和探针，直接利用遗传信息触发病变细胞的死亡。这个想法是利用疾病特异性的mRNA或DNA序列来指导前体药物和激活剂的结合，从而将前体药物转化为活性药物。在这种方法中，核酸不被用作靶标，而是作为触发器，因此不依赖于疾病特异性核酸序列的生物活性，仅依赖于其独特性和可及性。我们正在研究这种新概念在化疗中的可行性，其中前药成分由附着在PNA片段上的药物组成，该片段与特定疾病mRNA的一部分互补，激活成分由附着在PNA片段上的催化剂组成，该片段与mRNA的相邻部分互补。只有在患病细胞中，疾病特异性mRNA才能导致这两种成分结合，从而导致前药转化为细胞毒性药物并导致细胞死亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aim of this project is 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 pro-drug and an activator capable of converting the pro-drug 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 are investigating the feasibility of one formulation of this new concept to chemotherapy in which the pro-drug 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 i s c omplementary 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 pro-drug to a cytotoxic drug and death of the cell.