ArticleRNA (New York, N.Y.)2021
Understanding the characteristics of nonspecific binding of drug-like compounds to canonical stem-loop RNAs and their implications for functional cellular assays.
Article in RNA (New York, N.Y.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Machine Learning for RNA-Targeting Drug Design.Journal of chemical information and modeling · 2026Review
- Comparative analysis of alkyne- and desthiobiotinylated photoaffinity probes for chemotranscriptomic profiling.RSC chemical biology · 2026Article
- TetronicPharmaceutics · 2026Article
- Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.bioRxiv : the preprint server for biology · 2025Article
- Structure guided discovery of small molecule ligands targeting the oncomiR-1 NPSL2 hairpin.Scientific reports · 2025Article
- DRLiPS: a novel method for prediction of druggable RNA-small molecule binding pockets using machine learning.Nucleic acids research · 2025Article
- Structures of complete HIV-1 TAR RNA portray a dynamic platform poised for protein binding and structural remodeling.Nature communications · 2025Article
- Progress in antileishmanial drugs: Mechanisms, challenges, and prospects.PLoS neglected tropical diseases · 2025Review
- NMR structures and magnetic force spectroscopy studies of small molecules binding to models of an RNA CAG repeat expansion.bioRxiv : the preprint server for biology · 2024Article
- NMR characterization and ligand binding site of the stem-loop 2 motif from the Delta variant of SARS-CoV-2.RNA (New York, N.Y.) · 2024Article
- NMRRSC medicinal chemistry · 2024Article
- Structural and computational studies of HIV-1 RNA.RNA biology · 2024Review
- An RNA excited conformational state at atomic resolution.Nature communications · 2023Article
- Kinetic Resolution of the Atomic 3D Structures Formed by Ground and Excited Conformational States in an RNA Dynamic Ensemble.Journal of the American Chemical Society · 2023Article
- Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics studies.Nucleic acids research · 2023Article
- Deep structural insights into RNA-binding disordered protein regions.Wiley interdisciplinary reviews. RNA · 2022Review
- Cryo-EM as a powerful tool for drug discovery: recent structural based studies of SARS-CoV-2.Applied microscopy · 2021Review
- Exploring the Druggability of Conserved RNA Regulatory Elements in the SARS-CoV-2 Genome.Angewandte Chemie (International ed. in English) · 2021Article
- Design and Implementation of Synthetic RNA Binders for the Inhibition of miR-21 Biogenesis.ACS medicinal chemistry letters · 2021Article
- Frameworks for targeting RNA with small molecules.The Journal of biological chemistryReview
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to nonspecific binding of aminoglycosides and intercalators to many stem-loop RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities. However, target engagement and cellular selectivity assays are not routinely performed, and it is often unclear whether functional activity directly results from specific binding to the target RNA. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activities of distinct stem-loop RNAs, to bind and inhibit the cellular activities of two unrelated HIV-1 stem-loop RNAs: the transactivation response element (TAR) and the rev response element stem IIB (RREIIB). All compounds bound TAR and RREIIB in vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting off-target interactions consistent with nonspecific activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that aminoglycosides and drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, in contrast to ligands that specifically bind riboswitches. Our results demonstrate that drug-like molecules can nonspecifically bind stem-loop RNAs most likely through hydrogen bonding and electrostatic interactions and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.
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