RNA-SPECIFIC LIGANDS: AN APPROACH TO NEW ANTIVIRALS

RNA 特异性配体：新型抗病毒药物的开发方法

• 批准号: 6488786
• 负责人: PETER A. BEAL
• 金额: $ 15万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6488786
• 关键词: RNA; affinity chromatography; antiviral agents; combinatorial chemistry; drug design /synthesis /production; electrospray ionization mass spectrometry; intermolecular interaction; ligands; nuclear magnetic resonance spectroscopy; peptide library; technology /technique development

DESCRIPTION: Ribonucleic acid (RNA) function is central to all life, including that of viruses and bacteria. Antibacterial agents such as neomycin and erythromycin are examples of existing drugs that target sites in bacterial ribosomal RNAs. Unfortunately, bacteria are becoming increasingly resistant to these compounds via adaptation that allows for the modification of the RNA target or modification of the antibiotic. Human immunodeficiency virus (HIV), adenovirus (AV) and Epstein-Barr virus (EBV) are examples of human pathogens that all have unique RNA structures that appear necessary for replication. Each of these RNAs are potential targets for drug intervention. Unfortunately, our lack of understanding of the recognition of RNA by small molecules limits our ability to design high affinity ligands. The goal of this project is to identify low molecular weight ligands (<-l000 Da) that bind selectively to predefined RNA structures and inhibit the formation of protein-RNA complexes. This will be accomplished via the generation of structurally diverse libraries of molecules and the selection of library members with the requisite affinity and selectivity properties. The libraries are designed to contain intercalating ligands with appended functional groups capable of making specific contacts in the grooves of an RNA double helix. These experiments will ultimately lead to the ability to design and synthesize molecules that bind selectively to specific sequences of duplex RNA. In addition, these new compounds would have the potential to be developed into therapeutics for viral and bacterial infections.

描述：核糖核酸（RNA）的功能是所有生命的核心，包括 即病毒和细菌。抗菌剂如新霉素和 红霉素是靶向细菌内位点的现有药物的实例， 核糖体RNA。不幸的是，细菌对抗生素的抵抗力越来越强。 这些化合物通过适应允许RNA的修饰 抗生素的靶向或修饰。人体免疫缺陷病毒（艾滋病毒）， 腺病毒（AV）和EB病毒（EBV）是人类病原体的实例 它们都具有复制所必需的独特RNA结构。每个 这些RNA是药物干预的潜在靶点。不幸的是我们的 由于缺乏对小分子识别RNA的理解， 设计高亲和力配体的能力。该项目的目标是 鉴定低分子量配体（<~1000 Da），其选择性结合 预定义的RNA结构并抑制蛋白质-RNA复合物的形成。 这将通过生成结构多样的库来实现 以及选择具有所需亲和力的文库成员 和选择性性质。这些文库被设计成包含嵌入 具有附加的官能团的配体，其能够在 RNA双螺旋的凹槽。这些实验最终将导致 设计和合成分子的能力， 双链RNA的特定序列。此外，这些新化合物将具有 有可能被开发成病毒和细菌的治疗药物， 感染.