ArticleJournal of the American Chemical Society2020
Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing.
Article in Journal of the American Chemical Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 79 citations in OpenAlex.
- Review
- Specificity and exon target space of splicing modifying compounds.Nature communications · 2026Article
- Designing small molecules targeting a cryptic RNA binding site through base displacement.Nature chemical biology · 2026Article
- Comparative analysis of alkyne- and desthiobiotinylated photoaffinity probes for chemotranscriptomic profiling.RSC chemical biology · 2026Article
- Targeting RNA binding proteins with small-molecule inhibitors: Advances, challenges, and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- The kinase inhibitor palbociclib binds to HIV TAR RNA with very low nanomolar affinity and exquisite specificity.Nucleic acids research · 2026Article
- Site-Selective Ligand Selection by Mutational Profiling for Covalent RNA Targeting.Angewandte Chemie (International ed. in English) · 2026Article
- Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines.Nature chemistry · 2026Article
- SHAPE-Based Chemical Probes for Studying preQACS chemical biology · 2025Article
- Success and Limitations of Current Force Fields for the Description of RNA-Ligand Complexes.The journal of physical chemistry. B · 2025Article
- Discovery of small molecule probes targeting the 5' stem-loop in the yeast U4/U6 snRNA.bioRxiv : the preprint server for biology · 2025Article
- Aryl Guanyl Hydrazones: A Viable Strategy for Designing BBB-Permeable, Neuroactive Compounds?ACS chemical neuroscience · 2025Review
- Machine Learning-Augmented Molecular Dynamics Simulations (MD) Reveal Insights Into the Disconnect Between Affinity and Activation of ZTP Riboswitch Ligands.Angewandte Chemie (International ed. in English) · 2025Article
- Design of an Orally Bioavailable Small Molecule That Modulates the Microtubule-Associated Protein Tau's Pre-mRNA Splicing.ACS chemical biology · 2025Article
- The Druggable Transcriptome Project: From Chemical Probes to Precision Medicines.Biochemistry · 2025Review
- Mapping small molecule-RNA binding sites via Chem-CLIP synergized with capillary electrophoresis and nanopore sequencing.Nucleic acids research · 2025Article
- Strategies for programmable manipulation of alternative splicing.Current opinion in genetics & development · 2024Review
- Targeting RNA with small molecules, from RNA structures to precision medicines: IUPHAR review: 40.British journal of pharmacology · 2024Review
- NMR structures of small molecules bound to a model of a CUG RNA repeat expansion.Bioorganic & medicinal chemistry letters · 2024Review
- 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
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
Abstract
Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity.
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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.