Principles for targeting RNA with drug-like small molecules

By K. D. Warner, Christine E. Hajdin, Kevin M. Weeks. 2018

618 citations recorded by the source corpus.

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.

Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology

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In Molecular Biology

Citations in the corpus

Accurate RNA 3D structure prediction using a language model-based deep learning approach (2022, neutral): “Studies focusing on RNA targeting have demonstrated that it can be an important, druggable target for drug development 2–4 and a useful synthetic biology design element 5 .”
Non-coding RNAs in disease: from mechanisms to therapeutics (2023, positive): “The development of small-molecule inhibitors of miRNAs, which directly bind and inhibit the activity of an oncogenic or disease-causing miRNA (Box 1), has important advantages over the use of oligonucleotides, such as superior metabolic stability, solubility and bioavailability 277,289–291 .”
Pervasive tertiary structure in the dengue virus RNA genome (2018, background): “6) may also contain high information content pockets (31) that comprise novel RNA-directed drug targets.”
The Structure and Function of DNA G-Quadruplexes (2020, background): “ments, it has previously been realised that increased planarity and strongly p-stacking compounds leads to off-target activity and that these molecules are generally difficult to improve via further medicinal chemistry [37].”
Integrating end-to-end learning with deep geometrical potentials for ab initio RNA structure prediction (2022, positive): “For example, it is estimated that targeting RNAs with small molecules will expand the drug design landscape by more than an order of magnitude compared to traditional protein-targeted drug discovery 1 .”