ArticleNature chemistry2023
A two-residue nascent-strand steric gate controls synthesis of 2'-O-methyl- and 2'-O-(2-methoxyethyl)-RNA.
Article in Nature chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Emerging strategies and innovations in circular RNA synthesis.Molecular therapy. Nucleic acids · 2026Review
- A magic methyl effect in the active site of a methyltransferase ribozyme.Nature communications · 2026Article
- Single-residue engineering of Klenow fragment enables broad acceptance of chemically modified nucleotides.Nucleic acids research · 2026Article
- Beyond the Sequence: Chemical and Topological Design and Innovations in mRNA Therapeutics.Chemical reviews · 2026Review
- Advances and challenges in non-canonical nucleic acids data storage.Nature communications · 2026Review
- The impact of chemical modifications of antisense oligonucleotides on CTX-M-15 β-lactamase target affinity and expression of ceftriaxone-resistantNAR molecular medicine · 2026Article
- Enzymatic synthesis of key RNA therapeutic building blocks using simple phosphate donors.Nature communications · 2025Article
- 8-Oxo-7,8-dihydropurines as Building Blocks to Enhance the Selectivity of an RNA Aptamer for Aminoglycosides.ACS chemical biology · 2025Article
- The coming of age of DNA-based catalysts for therapeutic applications.Clinical and translational medicine · 2025Article
- Synthesis of 2-Substituted Adenosine Triphosphate Derivatives and their use in Enzymatic Synthesis and Postsynthetic Labelling of RNA.Chembiochem : a European journal of chemical biology · 2025Article
- Advancements in SELEX Technology for Aptamers and Emerging Applications in Therapeutics and Drug Delivery.Biomolecules · 2025Review
- Engineering a DNA polymerase for modifying large RNA at specific positions.Nature chemistry · 2025Article
- Measuring XNA polymerase fidelity in a hydrogel particle format.Nucleic acids research · 2025Article
- New Therapeutic Modalities in Prion Diseases.Sub-cellular biochemistry · 2025Review
- Catalyzing the future: recent advances in chemical synthesis using enzymes.Current opinion in chemical biology · 2024Review
- Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations.NPJ precision oncology · 2024Article
- Controlled enzymatic synthesis of oligonucleotides.Communications chemistry · 2024Review
- Polyamines promote xenobiotic nucleic acid synthesis by modified thermophilic polymerase mutants.RSC chemical biology · 2024Article
- Aptamer Technologies in Neuroscience, Neuro-Diagnostics and Neuro-Medicine Development.Molecules (Basel, Switzerland) · 2024Review
- MultiplexedNucleic acid therapeutics · 2024Article
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10 authors.
Funding
Abstract
Steric exclusion is a key element of enzyme substrate specificity, including in polymerases. Such substrate specificity restricts the enzymatic synthesis of 2'-modified nucleic acids, which are of interest in nucleic-acid-based drug development. Here we describe the discovery of a two-residue, nascent-strand, steric control 'gate' in an archaeal DNA polymerase. We show that engineering of the gate to reduce steric bulk in the context of a previously described RNA polymerase activity unlocks the synthesis of 2'-modified RNA oligomers, specifically the efficient synthesis of both defined and random-sequence 2'-O-methyl-RNA (2'OMe-RNA) and 2'-O-(2-methoxyethyl)-RNA (MOE-RNA) oligomers up to 750 nt. This enabled the discovery of RNA endonuclease catalysts entirely composed of 2'OMe-RNA (2'OMezymes) for the allele-specific cleavage of oncogenic KRAS (G12D) and β-catenin CTNNB1 (S33Y) mRNAs, and the elaboration of mixed 2'OMe-/MOE-RNA aptamers with high affinity for vascular endothelial growth factor. Our results open up these 2'-modified RNAs-used in several approved nucleic acid therapeutics-for enzymatic synthesis and a wider exploration in directed evolution and nanotechnology.
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