Selective Recognition of Folded RNA by Small Oligomers

新的药物靶点是重要的研究，以找到新的和更有效的疗法，以减轻人类疾病。 目前，RNA和相关的RNA结合蛋白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这些结构的基本知识。 在我们的研究中，新型分子的RNA结合特性正在用HIV的TAR RNA进行检查。 与这些RNA结合的分子可能会关闭病毒的复制。从这项工作中开发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。 我们发现了一种新的分子，它与TAR RNA结合得非常好，并阻断了达特蛋白的结合。 在过去的一年里，我们一直在追求的小分子干扰核衣壳蛋白7，NCp 7，及其在包装病毒HIV RNA的协会的发展。 干扰这一过程是干扰HIV进展的另一种策略，我们的出版物《自然化学生物学》表明，小分子在防止HIV复制方面的机制涉及一种独特的再酰化途径。 我们继续开发这种小分子，并正在探索转化工作，以检查机制和任何相关毒性的更多细节。

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.