ArticleProceedings of the National Academy of Sciences of the United States of America2022
SHAPE-enabled fragment-based ligand discovery for RNA.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Mammalian therapeutic riboswitches: Engineering and custom ligands.Molecular therapy. Nucleic acids · 2026Review
- Comparative Evaluation of Explicit Solvent Models for RNA-Ligand Docking.Journal of chemical information and modeling · 2026Article
- Mechanistically Defined Epoxide- and Aziridine-2-carboxamide Electrophiles Enable Stereoselective Covalent Ribonucleic Acid Modulation.Journal of the American Chemical Society · 2026Article
- Structure and sequence characteristics of 5'-stem-loop 1 modulate the escape from nsp1-mediated repression in SARS-CoV-2 variants.Nucleic acids research · 2026Article
- RNA functional modulation by Mitoxantrone via RNA structural ensemble repartitioning.Nature communications · 2026Article
- Systematic identification of variant-specific RNA structure-small molecule interactions exemplified by RNA G-quadruplexes.Nature communications · 2026Article
- SHAPE-Based Chemical Probes for Studying preQACS chemical biology · 2025Article
- Structure-Guided Design of a Bioactive Covalent Small Molecule Targeting a Riboswitch.Journal of the American Chemical Society · 2025Article
- Discovery of Macrocyclic Peptide Binders, Covalent Modifiers, and Degraders of a Structured RNA by mRNA Display.Journal of the American Chemical Society · 2025Article
- Streamlined Fragment-Based Discovery Platform for Targeting Structured RNAs.ACS chemical biology · 2025Article
- Structure-informed design of an ultrabright RNA-activated fluorophore.Nature chemistry · 2025Article
- RNA G-quadruplex structure targeting and imaging: recent advances and future directions.RNA (New York, N.Y.) · 2025Review
- Stacking Interactions of Druglike Heterocycles with Nucleobases.Journal of chemical information and modeling · 2025Article
- Binding-Site Purification of Actives (B-SPA) Enables Efficient Large-Scale Progression of Fragment Hits by Combining Multi-Step Array Synthesis With HT Crystallography.Angewandte Chemie (International ed. in English) · 2025Article
- DRLiPS: a novel method for prediction of druggable RNA-small molecule binding pockets using machine learning.Nucleic acids research · 2025Article
- The Unpaved Road of Non-Coding RNA Structure-Function Relationships: Current Knowledge, Available Methodologies, and Future Trends.Non-coding RNA · 2025Review
- TheRNA (New York, N.Y.) · 2024Article
- Disulfide Tethering to Map Small Molecule Binding Sites Transcriptome-wide.ACS chemical biology · 2024Article
- Characterization of the dual regulation by a c-di-GMP riboswitch Bc1 with a long expression platform fromMicrobiology spectrum · 2024Article
- Competitive Microarray Screening Reveals Functional Ligands for the DHX15 RNA G-Quadruplex.ACS medicinal chemistry letters · 2024Article
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
The transcriptome represents an attractive but underused set of targets for small-molecule ligands. Here, we devise a technology that leverages fragment-based screening and SHAPE-MaP RNA structure probing to discover small-molecule fragments that bind an RNA structure of interest. We identified fragments and cooperatively binding fragment pairs that bind to the thiamine pyrophosphate (TPP) riboswitch with millimolar to micromolar affinities. We then used structure-activity relationship information to efficiently design a linked-fragment ligand, with no resemblance to the native ligand, with high ligand efficiency and druglikeness, that binds to the TPP thiM riboswitch with high nanomolar affinity and that modulates RNA conformation during cotranscriptional folding. Principles from this work are broadly applicable, leveraging cooperativity and multisite binding, for developing high-quality ligands for diverse RNA targets.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.