ArticleNucleic acids research2003
Expanding the design horizon of antisense oligonucleotides with alpha-L-LNA.
Article in Nucleic acids research, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 85 citations in OpenAlex.
- Guanine base modifications in antisense oligonucleotides mitigate acute central nervous system toxicity.RSC chemical biology · 2026Article
- Development of bioconjugate-based delivery systems for nucleic acids.RNA (New York, N.Y.) · 2024Review
- An enhanced biophysical screening strategy to investigate the affinity of ASOs for their target RNA.RSC chemical biology · 2023Article
- The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides.Pharmaceuticals (Basel, Switzerland) · 2022Review
- The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery.Biomedicines · 2021Review
- Cellular Targeting of Oligonucleotides by Conjugation with Small Molecules.Molecules (Basel, Switzerland) · 2020Review
- Metallacarborane Complex Boosts the Rate of DNA Oligonucleotide Hydrolysis in the Reaction Catalyzed by Snake Venom Phosphodiesterase.Biomolecules · 2020Article
- Chemical Diversity of Locked Nucleic Acid-Modified Antisense Oligonucleotides Allows Optimization of Pharmaceutical Properties.Molecular therapy. Nucleic acids · 2020Article
- Gymnotic Delivery of LNA Mixmers Targeting Viral SREs Induces HIV-1 mRNA Degradation.International journal of molecular sciences · 2019Article
- Target RNA-directed microRNA degradation; which controls which?Non-coding RNA investigation · 2018Article
- Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy.Molecular therapy. Nucleic acids · 2017Article
- Development of Antisense Drugs for Dyslipidemia.Journal of atherosclerosis and thrombosis · 2016Review
- A cytoplasmic pathway for gapmer antisense oligonucleotide-mediated gene silencing in mammalian cells.Nucleic acids research · 2015Article
- Advanced In vivo Use of CRISPR/Cas9 and Anti-sense DNA Inhibition for Gene Manipulation in the Brain.Frontiers in genetics · 2015Review
- C5-alkynyl-functionalized α-L-LNA: synthesis, thermal denaturation experiments and enzymatic stability.The Journal of organic chemistry · 2014Article
- A Kinetic Model Explains Why Shorter and Less Affine Enzyme-recruiting Oligonucleotides Can Be More Potent.Molecular therapy. Nucleic acids · 2014Article
- Article
- Locked and unlocked nucleosides in functional nucleic acids.Molecules (Basel, Switzerland) · 2011Article
- Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates.Nucleic acids research · 2010Article
- Functionalized 2'-amino-alpha-L-LNA: directed positioning of intercalators for DNA targeting.The Journal of organic chemistry · 2009Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oligonucleotides containing Locked Nucleic Acids (LNA) to various extents and at various positions were evaluated for antisense activity, RNase H recruitment, nuclease stability and thermal affinity. In this work, two different diastereoisomers of LNA were studied: the beta-D-LNA and the alpha-L-LNA (abbreviated as beta-D-LNA and alpha-L-LNA). Our findings show that the best antisense activity with 16mer gapmers containing beta-D-LNA (oligonucleotides containing consecutive segments of LNA and DNA with a central DNA stretch flanked by two LNA segments, LNA-DNA-LNA) is found with gap sizes between 7 and 10 nt. The optimal gap size is motif-dependent, and requires the right balance between gap size and affinity. Compared to beta-D-LNA, alpha-L-LNA shows superior stability against a 3'-exonuclease. The design possibilities of alpha-L-LNA were explored for different gapmers and other designs, collectively called chimeras. The placement of alpha-L-LNA in the junctions or in the flanks resulted in potent antisense oligonucleotides. Moreover, different chimeras with an alternate composition of DNA, alpha-L-LNA and beta-D-LNA were evaluated in terms of antisense activity and RNase H recruitment. Chimeras with an interrupted DNA stretch with alpha-L-LNA still recruit RNase H and show good levels of antisense activity, while the same design with beta-D-LNA results in a drop in antisense potency. Our findings indicate that alpha-L-LNA is a powerful and versatile nucleotide analogue for designing potent antisense oligonucleotides.
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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.