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Inhibition of RNA-binding proteins with small molecules

Abstract

Protein–RNA interactions have crucial roles in various cellular activities, which, when dysregulated, can lead to a range of human diseases. The identification of small molecules that target the interaction between RNA-binding proteins (RBPs) and RNA is progressing rapidly and represents a novel strategy for the discovery of chemical probes that facilitate understanding of the cellular functions of RBPs and of therapeutic agents with new mechanisms of action. In this Review, I present a current overview of targeting emerging RBPs using small-molecule inhibitors and recent progress in this burgeoning field. Small-molecule inhibitors that were reported for three representative emerging classes of RBPs, the microRNA-binding protein LIN28, the single-stranded or double-stranded RNA-binding Toll-like receptors and the CRISPR-associated (Cas) proteins, are highlighted from a medicinal-chemistry and chemical-biology perspective. However, although this field is burgeoning, challenges remain in the discovery and characterization of small-molecule inhibitors of RBPs.

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Fig. 1: Selected strategies for targeting protein–RNA interactions.
Fig. 2: Timeline of major advances in the development of small-molecule inhibitors that target RBPs.
Fig. 3: Small-molecule RBP inhibitors and SMN2 splicing modulators.
Fig. 4: Structure of the human LIN28–preE-let-7f-1 microRNA complex.
Fig. 5: High-throughput screening approaches to identify LIN28 inhibitors.
Fig. 6: Small-molecule inhibitors of the microRNA-binding LIN28 proteins.
Fig. 7: Structures of Toll-like receptor complexes.
Fig. 8: Small-molecule inhibitors of Toll-like receptors.
Fig. 9: Small-molecule inhibitors of PKR.
Fig. 10: Structures of selected Cas complexes.
Fig. 11: Small-molecule inhibitors of Cas9.

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Acknowledgements

The author gratefully acknowledges financial support from AstraZeneca, Merck KGaA, Pfizer Inc. and the Max Planck Society. The author thanks L. Borgelt and J. Hwang for assistance in the preparation of figures and critical reading, H. Lightfoot and D. Lim for discussions on the LIN28–let-7 interaction, P. ‘t Hart and J. Imig for discussions on RNA-binding proteins and protein–RNA interactions, and P. Hommen for proofreading. The author would like to thank the anonymous reviewers for their thought-provoking comments and apologize to colleagues whose work was not cited owing to selected coverage.

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Glossary

RNA-binding proteins

(RBPs). Proteins that contain various structural motifs that directly bind to ribonucleic acid. RBPs are a part of ribonucleoprotein complexes and regulate the metabolism of cellular RNAs.

Ribonucleoprotein

A nuclear or cytoplasmic complex of RNAs and RNA-binding proteins.

MicroRNA

(miRNA). Small non-coding RNA containing about 22 nucleotides, which negatively regulates gene targets.

Non-coding RNA

(ncRNA). RNA that is not translated into a protein. Major classes of ncRNAs include ribosomal RNAs, transfer RNAs, long non-coding RNAs and small non-coding RNAs.

Clustered regularly interspaced short palindromic repeats

(CRISPR). A series of short, repeating DNA sequences in the prokaryotic genome that are a hallmark of prokaryotic adaptive immune systems, in which CRISPR-associated (Cas) proteins recognize and bind to CRISPR RNA sequences as a guide to perform site-specific cleavage of external nucleic acids.

Post-transcriptional regulators

Regulate RNA metabolism by various chemical changes catalysed by RNA-binding proteins on primary transcript of RNAs following transcription from a gene.

Electrophoretic mobility shift assay

(EMSA). A method using a labelled nucleic acid to detect protein–nucleic-acid complexes, which migrate slower than the free nucleic acid in non-denaturing gel electrophoresis.

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Wu, P. Inhibition of RNA-binding proteins with small molecules. Nat Rev Chem 4, 441–458 (2020). https://doi.org/10.1038/s41570-020-0201-4

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