Harnessing Small Molecules to Probe the Structure and Function of Regulatory RNAs

利用小分子探测调节 RNA 的结构和功能

• 批准号: 10405219
• 负责人: Amanda E Hargrove
• 金额: $ 42.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405219
• 关键词: 2019-nCoV; Automobile Driving; Bacterial Infections; Binding; Biological; Biological Assay; Biological Process; Biology; Cells; Chemicals; Complex; Development; Disease; Disseminated Malignant Neoplasm; Enterovirus 71; Explosion; HIV; Health; Human; Lead; Libraries; Ligands; Machine Learning; Methods; Molecular Biology; Molecular Conformation; Neuromuscular Diseases; Oncogenic; Pattern Recognition; Property; Proteins; Protocols documentation; Quantitative Structure-Activity Relationship; RNA; RNA Binding; RNA Conformation; RNA-targeting therapy; Research; Scientist; Structure; Techniques; Therapeutic; Translations; Untranslated RNA; Viral; Virus Diseases; Virus Replication; Work; bacterial resistance; base; human disease; improved; insight; interdisciplinary approach; interest; programs; scaffold; screening; small molecule; success; tool

PROJECT SUMMARY Despite the recent explosion of interest in RNA targeting, therapeutic potential is presently limited by a lack of fundamental understanding of how to achieve selective and functional small molecule targeting. The overarching focus of our research program is to elucidate the key drivers of selectivity in small molecule:RNA recognition and to apply these principles to facilitate development of RNA-targeted chemical probes and therapeutics that modulate RNA function. To begin, we identified physicochemical, structural, and spatial properties of biologically active RNA ligands that are distinct from those of protein-targeted ligands. Synthetic elaboration of RNA binding scaffolds into a library enriched with these properties has led to improved recognition of disease relevant RNA, including viral and long noncoding RNA structures. We used pattern recognition protocols to identify RNA topologies that can be differentially recognized by small molecules and have elaborated this technique to visualize conformational changes. This combined work has led to remarkable successes such as the targeting of enterovirus 71 RNA, where our ligand induced a dramatic conformation change that increased binding of a repressive human protein, decreased viral translation, and inhibited viral replication. Our approach is also showing preliminary success against SARS-CoV2 regulatory RNA. Building off these accomplishments, we propose to develop new libraries and screening methods to understand functional selectivity against a range of more complex tertiary and quaternary structures. Insights into the most critical driving factors will be revealed through pattern recognition / machine learning analysis as well as through an ensemble-based QSAR method that will allow rational targeting of any RNA. Key determinants of biological selectivity will be revealed in high throughput cell-based assays. These discoveries will be further enhanced by elucidation of the structure-dynamics-function relationships of oncogenic long noncoding RNAs. Our tools have lowered barriers to the discovery of selective RNA ligands. The proposed work will finally open a new horizon in RNA-targeting, in which chemical and biological scientists will readily and productively screen for small molecule probes against a wide range of RNA molecules, including those relevant to human disease. Such capabilities will allow the therapeutic potential of RNA to be fully exploited and inherently transform our understanding of molecular biology.

项目总结