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。我们发现了一种新的分子，它与TAR RNA结合得非常好，并阻止了TAT蛋白的结合。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，显示出非常好的活性。我们已经完成了一项关于这些分子对外周血单个核细胞(PBMC)抗病毒作用的广泛研究，PBMC是含有HIV喜欢感染的CD4细胞的白细胞集合。我们的分子对PBMC具有良好的活性，毒性低，并且我们的分子对一系列不同的HIV毒株(8种不同的HIV毒株)都具有活性。关于这项研究的一篇论文已经提交。我们正在继续优化我们的分子的生物活性，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。我们还在合作调查HIV是否会随着时间的推移而对我们的分子产生抗药性。

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. 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 very good activity. We have completed an extensive study on the antiviral effects of these molecules on peripheral blood mononuclear cells (PBMCs), which are collections of white blood cells containing the CD4 cells that HIV likes to infect. Our molecules have good activity with low toxicity on PBMCs, and our molecules are active across a range of different HIV strains (8 different clades of HIV). A paper on this research has been submitted. We are continuing to optimize the biological activity of our molecules and we are pursuing fundamental studies to understand the molecular recognition properties of our molecules for TAR RNA. We are also collaborating to investigate whether HIV resistance to our molecules emerges over time.