ArticleNature biotechnology2017
Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides.
Article in Nature biotechnology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 171 papers.
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Who cites it
171 citing papers in PubMed.
- A Pharmacological Batch of Mongersen that Downregulates Smad7 is Effective as Induction Therapy in Active Crohn's Disease: A Phase II, Open-Label Study.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2021Trial
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- Design and Synthesis of Phosphonoproline-Proline Bioisosteric Mimetics of Proline Dimers: Pseudopeptide Constructs as Potential Inhibitors of the Zn-Metalloprotease PPEP‑1 Associated withACS medicinal chemistry letters · 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
- Synthesis of highly complex phosphorothioate-modified oligonucleotides on microarrays.Scientific reports · 2026Article
- Antisense Oligonucleotides: Technological Advances, Clinical Progress, and Expanding Therapeutic Frontiers.Pharmaceutics · 2026Review
- Current CMC challenges in oligonucleotide API development: from IND to NDA.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Chemical cleavage coupled with LCMS to report on the true diastereomeric distributions of phosphorothioate linkages in gapmer ASO.Analytical and bioanalytical chemistry · 2026Article
- Stereocontrolled Synthesis of Dimethylamino Phosphorochloridate Monomers toward Stereopure Phosphorodiamidate Morpholino Oligonucleotides.The Journal of organic chemistry · 2026Article
- Navigating the next frontier in biomedicine: breakthroughs and insights in nucleic acid therapeutics.Chemical science · 2026Review
- Comparative Characterization of a Proposed Generic Nusinersen: Identity of the Oligonucleotide Structure and Equivalence in SMN2 Splicing Activity.Pharmaceutics · 2026Article
- The use of multiple liquid chromatography methods augmented by phosphorus-31 nuclear magnetic resonance to characterize the diastereomer composition in synthetic oligonucleotides.Journal of chromatography. A · 2026Article
- CMsiRNAdb: a database of chemically modified SiRNA silencing efficiency for nucleic acid drug design.BMC bioinformatics · 2026Article
- Development of Antisense Gapmers for the Treatment of Huntington's Disease.Methods in molecular biology (Clifton, N.J.) · 2026Article
- RNA-based therapeutic opportunities for the treatment of kidney diseases.Nature reviews. Nephrology · 2026Review
- Chalcogen-modified Nucleic Acid Analogues.Current medicinal chemistry · 2026Article
- Expanded genetic alphabet increases structural and chemical diversity of six-letter DNA for high-affinity protein-targeting aptamers.Nature communications · 2025Article
- Review
111 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3'-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.
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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.