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Targeting RNA structures with small molecules

Nature Reviews Drug Discovery volume 21, pages 736–762 (2022)Cite this article

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Abstract

RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing — by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.

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Fig. 1: Human RNAs regulate key biological processes, and their functions are driven by their structures.
Fig. 2: Methods to identify or design small-molecule RNA binders.
Fig. 3: Methods of target validation for small molecules that target RNA.
Fig. 4: Strategies for lead optimization of RNA-targeted small molecules.
Fig. 5: Small-molecule binding to RNA structures elicits biological effects through various modes of action.
Fig. 6: Small-molecule RNA degraders and their mechanisms of action.

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Acknowledgements

This work was funded by the NIH (R35 NS116846, R01 CA249180, UG3 NS116921 and P01 NS099114 to M.D.D. and R01 GM073850 to R.T.B.) and the Department of Defense (W81XWH-19-1-0719 and W81XWH-20-1-0727 to M.D.D).

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Author notes

  1. These authors jointly supervised this work: Robert T. Batey and Matthew D. Disney.

Authors and Affiliations

  1. Department of Chemistry, Scripps Research, Jupiter, FL, USA

    Jessica L. Childs-Disney, Xueyi Yang, Quentin M. R. Gibaut, Yuquan Tong & Matthew D. Disney

  2. Department of Biochemistry, University of Colorado, Boulder, CO, USA

    Robert T. Batey

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Correspondence to Robert T. Batey or Matthew D. Disney.

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M.D.D. is a founder of Expansion Therapeutics. R.T.B. serves on the Scientific Advisory Board of Expansion Therapeutics and MeiraGTx. The remaining authors declare no competing interests.

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Glossary

Antisense oligonucleotides

(ASOs). Single-stranded DNA or RNA oligonucleotides, including combinations thereof that are chemically modified, that are complementary to the sequence of target RNA and can induce RNase H-mediated degradation or sterically block the ribosome.

Riboswitch

Region of RNA structure located in the 5′ leader of bacterial RNAs that undergoes conformational switching upon small-molecule binding to regulate translation.

Internal ribosome entry site

(IRES). RNA structural element typically in the 5′ untranslated region that can recruit ribosomes and initiate cap-independent translation.

MicroRNA

(miRNA). Short noncoding RNA that has important roles in mediating gene expression by guiding Argonaute proteins to their mRNA target via base pairing to the 3′ untranslated region. miRNAs are formed stepwise, first from primary miRNAs to precursor miRNAs by the nuclease Drosha; then from precursor to mature (functional) miRNAs by the nuclease Dicer.

Pharmacophore

3D arrangement of a molecule or molecular group that confers bioactivity via interactions with the compound’s target.

Transcriptome

A landscape of all RNAs transcribed from a genome.

Splicing modulators

Small molecules or proteins that are capable of directing RNA splicing by inducing inclusion or exclusion of exons.

Functional selectivity

A metric that compares the effect of a compound on the biological activity of the desired target versus its effect on other targets.

On- and off-targets

An on-target is the biomolecule that a compound is designed to modulate the function of; an off-target is unintendedly modulated by the small molecule.

RNA sequencing

(RNA-seq). A high-throughput method that analyses gene expression transcriptome-wide.

Phenotypic screening

A method that screens small molecules on the basis of a desired phenotypic outcome, without knowledge of its actual target.

Structure–activity relationship

(SAR). Approach that aims to correlate the chemical structure of a compound with its biological activity.

Ribonuclease-targeting chimeras

(RIBOTACs). Small-molecule chimeras that activate and recruit endogenous ribonucleases to an RNA target to trigger its degradation.

Gini coefficient

A statistical measurement that quantifies the selectivity of a small molecule, ranging from 0 to 1, where 0 indicates that the compound inhibits every drug target studied equally and 1 indicates a compound selective for one drug target.

Intrinsically disordered proteins

(IDPs). Proteins that lack well-defined 3D structures and are thus considered undruggable.

Iron-responsive elements

(IREs). Small stem–loop structures present in 5′ or 3′ untranslated regions (UTRs) that bind to iron regulatory proteins (IRPs). IRP binding to IREs in the 5′UTR prevents ribosome docking and blocks RNA translation whereas binding to the 3′UTR stabilizes the transcript and upregulates translation.

Proteolysis-targeting chimeras

(PROTACs). Chimeric molecules comprising a protein-binding module and a E3 ubiquitin ligase-recognition module, which tags the targeted protein for selective degradation by the proteasome.

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Childs-Disney, J.L., Yang, X., Gibaut, Q.M.R. et al. Targeting RNA structures with small molecules. Nat Rev Drug Discov 21, 736–762 (2022). https://doi.org/10.1038/s41573-022-00521-4

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