ArticleNucleic acids research2021
Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 121 citations in OpenAlex.
- Article
- Exploring the Potential of PhosphoramideACS omega · 2026Article
- Neutral Backbone Modifications Enhance the Pharmacokinetics and Biodistribution of Antibody-Oligonucleotide Conjugates with High Drug-to-Antibody Ratios.Journal of medicinal chemistry · 2026Article
- 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
- 5'-Palmitate Lipid and Internal LNA-Piperidyl Triesters Enhance the RNA Affinity and Activity of Splice-Switching Oligonucleotides.Journal of the American Chemical Society · 2026Article
- The Versatile Applications of Antisense Oligonucleotides in Modern Medicine.International journal of molecular sciences · 2026Review
- Phosphorothioate antisense oligonucleotide induced innate immune activation is attenuated by tryptophan oxidation products.Nucleic acids research · 2026Article
- Antisense oligonucleotide-mediated knockdown therapy in two infants with severe KCNT1 epileptic encephalopathy.Nature medicine · 2026Article
- Strengthening Antisense Oligonucleotide-Mediated Anti-Tumor Immunity via Metal-Organic Framework Nanoparticles.Nano letters · 2026Article
- Expanding the Range of Methods for Obtaining Diverse Representatives of Sulfonyl Phosphoramidate Oligonucleotides.ACS omega · 2026Article
- The efficacy of oligonucleotide-based gene therapeutics in gene silencing.Theranostics · 2026Review
- Structural and Physicochemical Optimization of Next-Generation Antisense Oligonucleotide with BROTHERS for Mitigating Off-Target Effects.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Tissue Pharmacokinetics of Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Unraveling and controlling late-onset neurotoxicity of antisense oligonucleotides through strategic chemical modifications.Molecular therapy. Nucleic acids · 2025Article
- RNA chemistry and therapeutics.Nature reviews. Drug discovery · 2025Review
- Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia.Nucleic acids research · 2025Article
- Article
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- Alternative transcription increases isoform complexity in Long Non-Coding RNAs and alters their functions in cancer.Non-coding RNA research · 2025Review
22 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect.
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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.