Department of Chemistry, Duke University, 124 Science Drive, Box 90346, Durham, NC 27708, USA.
Chem Commun (Camb). 2020 Nov 26;56(94):14744-14756. doi: 10.1039/d0cc06796b.
The structural and regulatory elements in therapeutically relevant RNAs offer many opportunities for targeting by small molecules, yet fundamental understanding of what drives selectivity in small molecule:RNA recognition has been a recurrent challenge. In particular, RNAs tend to be more dynamic and offer less chemical functionality than proteins, and biologically active ligands must compete with the highly abundant and highly structured RNA of the ribosome. Indeed, the only small molecule drug targeting RNA other than the ribosome was just approved in August 2020, and our recent survey of the literature revealed fewer than 150 reported chemical probes that target non-ribosomal RNA in biological systems. This Feature outlines our efforts to improve small molecule targeting strategies and gain fundamental insights into small molecule:RNA recognition by analyzing patterns in both RNA-biased small molecule chemical space and RNA topological space privileged for differentiation. First, we synthesized libraries based on RNA binding scaffolds that allowed us to reveal general principles in small molecule:recognition and to ask precise chemical questions about drivers of affinity and selectivity. Elaboration of these scaffolds has led to recognition of medicinally relevant RNA targets, including viral and long noncoding RNA structures. More globally, we identified physicochemical, structural, and spatial properties of biologically active RNA ligands that are distinct from those of protein-targeted ligands, and we have provided the dataset and associated analytical tools as part of a publicly available online platform to facilitate RNA ligand discovery. At the same time, 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 in RNA secondary structure. These fundamental insights into the drivers of RNA recognition in vitro have led to functional targeting of RNA structures in biological systems. We hope that these initial guiding principles, as well as the approaches and assays developed in their pursuit, will enable rapid progress toward the development of RNA-targeted chemical probes and ultimately new therapeutic approaches to a wide range of deadly human diseases.
在治疗相关的 RNA 中，结构和调节元件为小分子靶向提供了许多机会，但对小分子与 RNA 识别的选择性驱动因素的基本理解一直是一个反复出现的挑战。特别是，RNA 往往比蛋白质更具动态性，提供的化学功能也更少，而且生物活性配体必须与核糖体中丰富且高度结构化的 RNA 竞争。事实上，除了核糖体之外，唯一靶向 RNA 的小分子药物是在 2020 年 8 月才获得批准的，而我们最近对文献的调查显示，在生物系统中靶向非核糖体 RNA 的报告化学探针还不到 150 个。本文概述了我们通过分析 RNA 偏向小分子化学空间和 RNA 拓扑空间中区分的模式，努力改进小分子靶向策略并深入了解小分子与 RNA 的识别。首先，我们基于 RNA 结合支架合成了文库，这使我们能够揭示小分子识别的一般原理，并对亲和力和选择性的驱动因素提出精确的化学问题。对这些支架的阐述导致了对医学相关 RNA 靶标的识别，包括病毒和长非编码 RNA 结构。更广泛地说，我们确定了生物活性 RNA 配体的物理化学、结构和空间特性与靶向蛋白质的配体不同，并且我们提供了数据集和相关分析工具作为一个公共在线平台的一部分，以促进 RNA 配体的发现。同时，我们使用模式识别协议来识别可以被小分子差异识别的 RNA 拓扑结构，并对该技术进行了阐述，以可视化 RNA 二级结构的构象变化。这些关于 RNA 识别的体外驱动因素的基本见解已经导致了在生物系统中对 RNA 结构的功能靶向。我们希望这些初步的指导原则以及在追求这些原则过程中开发的方法和测定方法，将能够促进 RNA 靶向化学探针的快速发展，并最终为广泛的致命人类疾病开发新的治疗方法。
