ArticleNucleic acids research2019
Site-specific replacement of phosphorothioate with alkyl phosphonate linkages enhances the therapeutic profile of gapmer ASOs by modulating interactions with cellular proteins.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed.
- Chemically stabilized long antisense oligonucleotides perturb RNA exosome function.Nucleic acids research · 2026Article
- Engineering the Future of Precision Medicine: A Comprehensive Guide to RNA Therapeutics.Current issues in molecular biology · 2026Review
- Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.Molecules (Basel, Switzerland) · 2026Review
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- The Versatile Applications of Antisense Oligonucleotides in Modern Medicine.International journal of molecular sciences · 2026Review
- Enhanced splicing modulation by NMA-modified antisense oligonucleotides.Nucleic acids research · 2026Article
- Evolution of siRNA Therapeutics: From Mechanistic Foundations to Clinical Expansion.Pharmaceutics · 2026Review
- Amidation of Phosphonoacetate-Modified Oligonucleotides and Evaluation of the Properties of the Synthesized Oligonucleotides.Organic letters · 2026Article
- Development and Validation of an Ion-Pair Reverse-Phase High-Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry Method for Determination of Purity of Nusinersen for Quality Control of Drug Substance or Drug Product.International journal of molecular sciences · 2026Article
- Advances in nano-delivery systems for overcoming the challenges of applying siRNA drugs in tumor therapy.Asian journal of pharmaceutical sciences · 2026Review
- Heteroduplex oligonucleotide technology boosts gene knockdown in cardiac and skeletal muscles.Nucleic acids research · 2026Article
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Synthesis, Biological Activity, and Molecular Dynamics Simulations of LNA-Charge Neutral Linkages for Enhanced Splice-Switching Antisense Oligonucleotides.Angewandte Chemie (International ed. in English) · 2025Article
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- Application of Antisense Oligonucleotides as an Alternative Approach for Gene Expression Control and Functional Studies.International journal of molecular sciences · 2025Review
- Article
- Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo.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
- Synthesis ofThe Journal of organic chemistry · 2025Article
- Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile.Nucleic acids research · 2025Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phosphorothioate-modified antisense oligonucleotides (PS-ASOs) interact with a host of plasma, cell-surface and intracellular proteins which govern their therapeutic properties. Given the importance of PS backbone for interaction with proteins, we systematically replaced anionic PS-linkages in toxic ASOs with charge-neutral alkylphosphonate linkages. Site-specific incorporation of alkyl phosphonates altered the RNaseH1 cleavage patterns but overall rates of cleavage and activity versus the on-target gene in cells and in mice were only minimally affected. However, replacing even one PS-linkage at position 2 or 3 from the 5'-side of the DNA-gap with alkylphosphonates reduced or eliminated toxicity of several hepatotoxic gapmer ASOs. The reduction in toxicity was accompanied by the absence of nucleolar mislocalization of paraspeckle protein P54nrb, ablation of P21 mRNA elevation and caspase activation in cells, and hepatotoxicity in mice. The generality of these observations was further demonstrated for several ASOs versus multiple gene targets. Our results add to the types of structural modifications that can be used in the gap-region to enhance ASO safety and provide insights into understanding the biochemistry of PS ASO protein interactions.
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Registered trials
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