ArticleNucleic acids research2018
Structural basis for the synergy of 4'- and 2'-modifications on siRNA nuclease resistance, thermal stability and RNAi activity.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 44 citations in OpenAlex.
- Emerging strategies and innovations in circular RNA synthesis.Molecular therapy. Nucleic acids · 2026Review
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- High-fidelity molecular decoding through tile-guided in situ self-assembly.Science advances · 2026Article
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- CMsiRNAdb: a database of chemically modified SiRNA silencing efficiency for nucleic acid drug design.BMC bioinformatics · 2026Article
- 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
- C‑Nucleosides Stabilize RNA by Reducing Nucleophilicity at 2'-OH.ACS central science · 2025Article
- Clickable RNA via 4'-Bioconjugate chemistry · 2025Article
- Control of ADAR2 Dimerization and RNA Editing Efficiency by Site-Specific 2'-Fluoro Modification of Guide RNAs.ACS chemical biology · 2025Article
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- Albumin-conjugation enables improved tumor targeting of aptamers via SPECT imaging.Molecular therapy. Nucleic acids · 2025Article
- Application of 4'-RSC advances · 2024Article
- Aptamers in neuro-oncology: An emerging therapeutic modality.Neuro-oncology · 2024Review
- Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models.Nature communications · 2022Article
- Programmable manipulation of oligonucleotide-albumin interaction for elongated circulation time.Nucleic acids research · 2022Article
- Synthesis, gene silencing activity, thermal stability, and serum stability of siRNA containing four (RSC advances · 2022Article
- Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications.RNA biology · 2022Review
- siRNAs containing 2'-fluorinated Northern-methanocarbacyclic (2'-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2'-F-NMC NTPs.Nucleic acids research · 2021Article
- Pharmacokinetics and Proceedings in Clinical Application of Nucleic Acid Therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
- Beyond ribose and phosphate: Selected nucleic acid modifications for structure-function investigations and therapeutic applications.Beilstein journal of organic chemistry · 2021Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Chemical modification is a prerequisite of oligonucleotide therapeutics for improved metabolic stability, uptake and activity, irrespective of their mode of action, i.e. antisense, RNAi or aptamer. Phosphate moiety and ribose C2'/O2' atoms are the most common sites for modification. Compared to 2'-O-substituents, ribose 4'-C-substituents lie in proximity of both the 3'- and 5'-adjacent phosphates. To investigate potentially beneficial effects on nuclease resistance we combined 2'-F and 2'-OMe with 4'-Cα- and 4'-Cβ-OMe, and 2'-F with 4'-Cα-methyl modification. The α- and β-epimers of 4'-C-OMe-uridine and the α-epimer of 4'-C-Me-uridine monomers were synthesized and incorporated into siRNAs. The 4'α-epimers affect thermal stability only minimally and show increased nuclease stability irrespective of the 2'-substituent (H, F, OMe). The 4'β-epimers are strongly destabilizing, but afford complete resistance against an exonuclease with the phosphate or phosphorothioate backbones. Crystal structures of RNA octamers containing 2'-F,4'-Cα-OMe-U, 2'-F,4'-Cβ-OMe-U, 2'-OMe,4'-Cα-OMe-U, 2'-OMe,4'-Cβ-OMe-U or 2'-F,4'-Cα-Me-U help rationalize these observations and point to steric and electrostatic origins of the unprecedented nuclease resistance seen with the chain-inverted 4'β-U epimer. We used structural models of human Argonaute 2 in complex with guide siRNA featuring 2'-F,4'-Cα-OMe-U or 2'-F,4'-Cβ-OMe-U at various sites in the seed region to interpret in vitro activities of siRNAs with the corresponding 2'-/4'-C-modifications.
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