RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these RNAs with small molecules offers opportunities to therapeutically modulate numerous cellular processes, including those linked to 'undruggable' protein targets. Despite this promise, there is currently only a single class of human-designed small molecules that target RNA used clinically — the linezolid antibiotics. However, a growing number of small-molecule RNA ligands are being identified, leading to burgeoning interest in the field. Here, we discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures — namely, in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. If focus is placed on such druggable binding sites in RNA, extensive knowledge of the typical physicochemical properties of drug-like small molecules could then enable small-molecule drug discovery for RNA targets to become (only) roughly as difficult as for protein targets.

RNA分子对于细胞信息传递和基因调控至关重要，RNA已涉及许多人类疾病。信使RNA和非编码RNA包含高度结构化的元件，证据表明，这些结构中的许多结构对于功能都很重要。用小分子靶向这些RNA提供了机会来治疗性调节众多细胞过程，包括那些与“非药物”蛋白靶标相关的过程。尽管有这样的承诺，但目前只有一类人类设计的靶向临床使用的RNA的小分子-利奈唑胺抗生素。但是，正在鉴定越来越多的小分子RNA配体，从而引起了人们对该领域的浓厚兴趣。这里，我们讨论了发现靶向RNA的小分子药物的原理，并认为总体挑战在于确定合适的靶结构，即在具有高信息含量并因此具有合适的配体结合口袋的致病RNA中。如果将重点放在RNA中的此类可药物结合位点上，那么对类药物小分子的典型理化特性的广泛了解将使（针对）RNA靶标的小分子药物发现变得（仅）与蛋白质靶标一样困难。