ArticleJournal of the American Chemical Society2021
Rational Design of RNA Editing Guide Strands: Cytidine Analogs at the Orphan Position.
Article in Journal of the American Chemical Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 30 citations in OpenAlex.
- Synthesis of 2'-O,4'-Cα-Dimethyl Ribonucleoside Analogs and Their Effects on RNA and Modulation of ADAR Editing.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- RNA-based therapeutic opportunities for the treatment of kidney diseases.Nature reviews. Nephrology · 2026Review
- Clickable RNA via 4'-Bioconjugate chemistry · 2025Article
- Discovery and Tuning of RNA Editing Guides via High-Throughput Screening and Chemical Modification.Chembiochem : a European journal of chemical biology · 2025Article
- Evaluation of in vitro liver models and non-human primates for predicting ADAR RNA editing efficiency in human liver.Scientific reports · 2025Article
- Control of ADAR2 Dimerization and RNA Editing Efficiency by Site-Specific 2'-Fluoro Modification of Guide RNAs.ACS chemical biology · 2025Article
- Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo.Nature communications · 2025Article
- Phylogenetic and structural analysis of Hydra ADAR.Archives of biochemistry and biophysics · 2025Article
- Review
- Structural analysis of human ADAR2-RNA complexes by X-ray crystallography.Methods in enzymology · 2025Article
- An In Vitro RNA Editing-Based Reporter Assay for Transcriptional Activity of Therapeutic Gene in Gene Therapy Products.Molecules (Basel, Switzerland) · 2024Article
- Nucleoside Analogs in ADAR Guide Strands Enable Editing at 5'-GBiomolecules · 2024Article
- Rational design of base, sugar and backbone modifications improves ADAR-mediated RNA editing.Nucleic acids research · 2024Article
- Structural perspectives on adenosine to inosine RNA editing by ADARs.Molecular therapy. Nucleic acids · 2024Review
- An improved SNAP-ADAR tool enables efficient RNA base editing to interfere with post-translational protein modification.Nature communications · 2024Article
- Site-specific regulation of RNA editing with ribose-modified nucleoside analogs in ADAR guide strands.Nucleic acids research · 2024Article
- Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.Biomedicines · 2024Review
- Chemical Modifications in RNA: Elucidating the Chemistry of dsRNA-Specific Adenosine Deaminases (ADARs).Accounts of chemical research · 2023Article
- Amplifying gene expression with RNA-targeted therapeutics.Nature reviews. Drug discovery · 2023Review
- RNA editing: Expanding the potential of RNA therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Adenosine Deaminases Acting on RNA (ADARs) convert adenosine to inosine in double stranded RNA. Human ADARs can be directed to predetermined target sites in the transcriptome by complementary guide strands, allowing for the correction of disease-causing mutations at the RNA level. Here we use structural information available for ADAR2-RNA complexes to guide the design of nucleoside analogs for the position in the guide strand that contacts a conserved glutamic acid residue in ADARs (E488 in human ADAR2), which flips the adenosine into the ADAR active site for deamination. Mutating this residue to glutamine (E488Q) results in higher activity because of the hydrogen bond donating ability of Q488 to N3 of the orphan cytidine on the guide strand. We describe the evaluation of cytidine analogs for this position that stabilize an activated conformation of the enzyme-RNA complex and increase catalytic rate for deamination by the wild-type enzyme. A new crystal structure of ADAR2 bound to duplex RNA bearing a cytidine analog revealed a close contact between E488, stabilized by an additional hydrogen bond and altered charge distribution when compared to cytidine. In human cells and mouse primary liver fibroblasts, this single nucleotide modification increased directed editing yields when compared to an otherwise identical guide oligonucleotide. Our results show that modification of the guide RNA can mimic the effect of hyperactive mutants and advance the approach of recruiting endogenous ADARs for site-directed RNA editing.
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Registered trials
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