Selective Recognition of Folded RNA by Small Oligomers

几十年来，化学家们设计并合成了有机分子，这些分子可以结合到蛋白质的活性位点上，抑制蛋白质的功能。蛋白质采用具有独特结合口袋的折叠三维结构，这一事实使化学家能够开发出以高亲和力和特异性结合靶蛋白的小有机分子。由于RNA也可以具有折叠的三维结构，化学家应该可以设计出以高亲和力和特异性结合靶RNA的新分子。这些分子最终可能会演变成新型药物，通过靶向RNA发挥其生物学作用。由于RNA的生物物理性质与蛋白质非常不同，因此必须开发用于RNA结合的分子类型将与结合蛋白质的分子非常不同。目前，RNA作为药物开发的潜在靶标的利用率明显不足：很可能是因为缺乏关于如何设计分子以靶向折叠RNA的基本知识。在我们的研究中，侧链功能化的多胺的RNA结合特性正在与两个重要的RNA靶点进行研究：HIV的TAR RNA和RRE RNA。与这些RNA结合的分子可能会关闭病毒的复制。从这项工作中获得的基本知识最终将适用于其他RNA靶点，并将为设计选择性结合折叠RNA结构的分子提供一套通用指南。在过去的一年里，我们已经建立了一个新的分子库，可以筛选与TAR RNA选择性结合的分子，我们已经使用许多基本的生物化学方法验证了这种筛选策略。我们目前正在优化我们的初步线索，以获得更好的结合亲和力，我们正试图与细胞生物学家合作，研究这些分子在HIV感染细胞中的活性。

For several decades, chemists have designed and synthesized organic molecules that bind to the active sites of proteins and inhibit protein functions. The fact that proteins adopt folded, three-dimensional structures with unique binding pockets allows chemists to develop small organic molecules that bind with high affinity and specificity to a target protein. Because RNA can also possess folded, three-dimensional structures, it should be possible for chemists to design new molecules that bind a target RNA with high affinity and specificity. Such molecules could ultimately evolve into new types of drugs that exert their biological effects by targeting RNA. Since the biophysical properties of RNA are very different from proteins, the types of molecules that must be developed for RNA binding will be very different from the molecules that bind to proteins. 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 have established a new library of molecules that can be screened for selective binding to TAR RNA, and we have validated this screening strategy using a number of basic biochemical methods. We are currently optimizing our initial leads for better binding affinity, and we are trying to initiate a collaboration with cell biologists to study the activity of these molecules in HIV infected cells.