Selective Recognition of Folded RNA by Small Oligomers

目前，作为药物开发的潜在靶点，RNA的利用严重不足：最有可能的原因是缺乏关于如何设计分子来靶向折叠的RNA的基本知识。在我们的研究中，用两个重要的RNA靶标：HIV的TAR RNA和RRE RNA来检测侧链功能化多胺的RNA结合特性。与这些RNA结合的分子可能会阻止病毒的复制。从这项工作中获得的基本知识最终将适用于其他RNA靶标，并将为设计选择性结合折叠RNA结构的分子提供一套通用的指导方针。在过去的一年里，我们发现了一种新的分子版本，它与TAR RNA结合得非常好，并阻止了TAT蛋白的关联。与一个细胞生物学小组合作研究艾滋病毒感染细胞中这些分子的活性，显示出相当好的活性。我们正在继续优化我们的分子的生物活性，以最大限度地减少毒性，我们正在进行基础研究，以了解我们的分子对TAR RNA的分子识别特性。

Currently, RNA is significantly underutilized as a potential target for drug development: most likely because there exists a lack of basic knowledge about how one should design a molecule to target a folded RNA. In our research, the RNA-binding properties of sidechain-functionalized polyamines are being examined with two important RNA targets: TAR RNA and RRE RNA of HIV. Molecules that bind to these RNAs can potentially shut down replication of the virus. The basic knowledge that will be developed from this work will ultimately be applicable to other RNA targets, and will provide a general set of guidelines for designing molecules that selectively bind a folded RNA structure. Over the past year, we identified a new version of our molecules that binds extremely well to TAR RNA and blocks association of the tat protein. A collaboration with a cell biology group to study the activity of these molecules in HIV infected cells has demonstrated reasonably good activity. We are continuing to optimize the biological activity of our molecules to minimize toxicity and we are pursuing fundamental studies to understand the molecular recognition properties of our molecules for TAR RNA.