NUCLEIC ACID TRIGGERED DRUG & PROBE RELEASE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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剂和探针，这些药物和探针直接利用遗传信息来触发患病细胞的死亡。 该想法是利用疾病特异性mRNA或DNA序列来指导前药与能够将前药转化为活性药物的活化剂的缔合。 在该方法中，核酸不用作靶标，而是用作触发剂，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的一种化疗制剂的可行性，其中前药组分由连接到与疾病特异性mRNA的一个部分互补的PNA片段的药物组成，并且活化组分由连接到与mRNA的相邻部分互补的PNA片段的催化剂组成。 只有在患病细胞中，疾病特异性mRNA才能引起两种组分缔合，然后导致前药转化为细胞毒性药物和细胞死亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.