ArticleNucleic acids research2017
5΄-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo.
Article in Nucleic acids research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 123 citations in OpenAlex.
- A versatile strategy for oligonucleotide functionalization via on-support phosphitylation.Nature chemistry · 2026Article
- Synthesis of siRNAs containing carbocyclic nucleotides and the role of cyclopentane conformation in RNAi activity.RSC chemical biology · 2026Article
- RNA-Based Therapies for Inherited Metabolic Disorders.Journal of inherited metabolic disease · 2026Review
- Advancing the Landscape of RNAi Nanotherapeutics for Ischemic Heart Disease.Advanced materials (Deerfield Beach, Fla.) · 2026Review
- Organyl 5'-Phosphates in siRNA Guide Strands: Structure-Function Relationships Governing Anchoring in Argonaute 2 and Metabolic Stability.bioRxiv : the preprint server for biology · 2026Article
- Advances in nano-delivery systems for overcoming the challenges of applying siRNA drugs in tumor therapy.Asian journal of pharmaceutical sciences · 2026Review
- Presence of phosphodiester backbone, but not nucleobases, in the guide's 3' terminal region is necessary for RISC loading and target cleavage in vitro and in vivo.Nucleic acids research · 2026Article
- The efficacy of oligonucleotide-based gene therapeutics in gene silencing.Theranostics · 2026Review
- C16-siRNAs in Focus: Development of ALN-APP, a Promising RNAi-Based Therapeutic for Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- A novel bispecific siRNA concept: Efficient dual knockdown ofMolecular therapy. Nucleic acids · 2025Article
- Optimized chemical structure extends silencing duration of therapeutic siRNAs in dividing cancer and immune cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- RNA chemistry and therapeutics.Nature reviews. Drug discovery · 2025Review
- Knocking on Cells' Door: Strategic Approaches for miRNA and siRNA in Anticancer Therapy.International journal of molecular sciences · 2025Review
- Damage-associated molecular patterns (DAMPs) in diseases: implications for therapy.Molecular biomedicine · 2025Review
- Redesigning miR-34a: structural and chemical advances in the therapeutic development of an miRNA anti-cancer agent.Biochemical Society transactions · 2025Article
- Multimeric Conjugates Using Engineered Peptide Scaffolds for Efficient siRNA Delivery.Bioconjugate chemistry · 2025Article
- Design, pharmacology, and toxicology of a novel chemically modified siRNA targeting hepatic angiotensinogen.Molecular therapy. Nucleic acids · 2025Article
- Systematic Evaluation of Position-Specific Tolerability of Seven Backbone and Ribose Modifications in Fully Chemically Stabilized siRNAs.Nucleic acid therapeutics · 2025Article
- Important Aspects of siRNA Design for Optimal Efficacy In Vitro and In Vivo.International journal of cell biology · 2025Review
- The beauty of symmetry: siRNA phosphorodithioate modifications reduce stereocomplexity, ease analysis, and can improveMolecular therapy. Nucleic acids · 2024Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
5΄-Vinylphosphonate modification of siRNAs protects them from phosphatases, and improves silencing activity. Here, we show that 5΄-vinylphosphonate confers novel properties to siRNAs. Specifically, 5΄-vinylphosphonate (i) increases siRNA accumulation in tissues, (ii) extends duration of silencing in multiple organs and (iii) protects siRNAs from 5΄-to-3΄ exonucleases. Delivery of conjugated siRNAs requires extensive chemical modifications to achieve stability in vivo. Because chemically modified siRNAs are poor substrates for phosphorylation by kinases, and 5΄-phosphate is required for loading into RNA-induced silencing complex, the synthetic addition of a 5΄-phosphate on a fully modified siRNA guide strand is expected to be beneficial. Here, we show that synthetic phosphorylation of fully modified cholesterol-conjugated siRNAs increases their potency and efficacy in vitro, but when delivered systemically to mice, the 5΄-phosphate is removed within 2 hours. The 5΄-phosphate mimic 5΄-(E)-vinylphosphonate stabilizes the 5΄ end of the guide strand by protecting it from phosphatases and 5΄-to-3΄ exonucleases. The improved stability increases guide strand accumulation and retention in tissues, which significantly enhances the efficacy of cholesterol-conjugated siRNAs and the duration of silencing in vivo. Moreover, we show that 5΄-(E)-vinylphosphonate stabilizes 5΄ phosphate, thereby enabling systemic delivery to and silencing in kidney and heart.
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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.