Selective Recognition of Folded RNA by Small Oligomers

小寡聚体选择性识别折叠 RNA

• 批准号: 7593521
• 负责人: daniel appella
• 金额: $ 24.41万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593521
• 关键词: Active Sites; Adopted; Affinity; Binding; Biochemical; Biological; Cells; Cellular biology; Class; Collaborations; Development; Future; Goals; Growth; Guidelines; HIV; Knowledge; Libraries; Methods; Numbers; Pharmaceutical Preparations; Polyamines; Property; Proteins; RNA; RNA Binding; RNA Conformation; RNA Folding; Research; Screening procedure; Small RNA; Specificity; Structure; Tars; Virus Replication; Work; design; drug development; protein function; three dimensional structure

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 still optimizing our initial leads for better binding affinity. We have also initiated a collaboration with a cell biology group to study the activity of these molecules in HIV infected cells. In addition, we are starting a collaboration with NMR spectroscopists to study the conformation of RNA when our molecule binds.

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。 我们仍在优化我们的初步线索，以获得更好的结合亲和力。 我们还与一个细胞生物学小组合作，研究这些分子在HIV感染细胞中的活性。 此外，我们正在开始与NMR光谱学家合作，研究我们的分子结合时RNA的构象。