Selective Recognition of Folded RNA by Small Oligomers

研究新的药物靶点对于找到新的、更有效的治疗方法来减轻人类疾病是很重要的。目前，作为药物开发的潜在靶点，RNA和相关的RNA结合蛋白的利用严重不足：很可能是因为缺乏关于如何设计分子来针对这些结构的基本知识。在我们的研究中，正在用HIV的TAR RNA来检测新型分子的RNA结合特性。与这些RNA结合的分子可能会阻止病毒的复制。从这项工作中发展出来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。在过去的一年里，我们一直在开发一种小分子来干扰核衣壳蛋白7，NCp7，及其在包装病毒HIV RNA中的关联。干扰这一过程是干扰艾滋病毒进展的另一种策略，我们的出版物“自然化学生物学”表明，小分子防止艾滋病毒复制的机制涉及一条独特的反应途径。我们一直在继续开发这种小分子，并正在探索翻译工作，以检查更多细节的机制和任何相关的毒性。

New drug targets are important to study to find new and more effective therapies to alleviate human disease. Currently, RNA and associated RNA-binding proteins are 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 these structures. In our research, the RNA-binding properties of new types of molecules are being examined with TAR RNA of HIV. Molecules that bind to these RNAs can potentially shut down replication of the virus. The basic knowledge 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. In the past year, we have pursued the development of a small molecule to interfere with nucleocapid protein 7, NCp7, and its association in packaging viral HIV RNA. Interfering with this process is another strategy to interfere with HIV's progression and our publication Nature Chemical Biology shows the mechanism of the small molecule in preventing HIV replication involves a unique reacylation pathway. We have continued to develop this small molecule and are exploring translational work to examine more details of the mechanism and any associated toxicity.