ArticleMolecular therapy. Nucleic acids2020
Chemical Diversity of Locked Nucleic Acid-Modified Antisense Oligonucleotides Allows Optimization of Pharmaceutical Properties.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- Antisense Oligonucleotides: Technological Advances, Clinical Progress, and Expanding Therapeutic Frontiers.Pharmaceutics · 2026Review
- Development of ARL4C antisense oligonucleotide with reduced off-target effects and enhanced efficacy as an anti-cancer drug.In vitro cellular & developmental biology. Animal · 2026Article
- The efficacy of oligonucleotide-based gene therapeutics in gene silencing.Theranostics · 2026Review
- ASOptimizer: optimizing chemical diversity of antisense oligonucleotides through deep learning.Nucleic acids research · 2025Article
- Biological Significance and Therapeutic Promise of Programmed Ribosomal Frameshifting.International journal of molecular sciences · 2025Review
- Experimental and computational investigations of RNA duplexes containing N7-regioisomers of adenosine and LNA-adenosine.Nucleic acids research · 2025Article
- Structural Unfolding of G-Quadruplexes: From Small Molecules to Antisense Strategies.Molecules (Basel, Switzerland) · 2024Review
- Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine.Molecular therapy. Nucleic acids · 2024Article
- ASOptimizer: Optimizing antisense oligonucleotides through deep learning for IDO1 gene regulation.Molecular therapy. Nucleic acids · 2024Article
- Antisense and Functional Nucleic Acids in Rational Drug Development.Antibiotics (Basel, Switzerland) · 2024Review
- Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.Nature communications · 2023Article
- An enhanced biophysical screening strategy to investigate the affinity of ASOs for their target RNA.RSC chemical biology · 2023Article
- Gymnotic uptake of AntimiRs alter microRNA-34a levels in 2D and 3D epithelial cell culture.Molecular therapy. Nucleic acids · 2023Article
- Effects of hsa-piR-32877 Suppression with Antisense LNA GapmeRs on the Proliferation and Apoptosis of Human Acute Myeloid Leukemia Cells.International journal of molecular and cellular medicine · 2023Article
- Targeting SAM-I Riboswitch Using Antisense Oligonucleotide Technology for Inhibiting the Growth ofAntibiotics (Basel, Switzerland) · 2022Article
- Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides.Nucleic acids research · 2022Article
- Reduction of Off-Target Effects of Gapmer Antisense Oligonucleotides by Oligonucleotide Extension.Molecular diagnosis & therapy · 2022Article
- Protective effects of the notoginsenoside R1 on acute lung injury by regulating the miR-128-2-5p/Tollip signaling pathway in rats with severe acute pancreatitis.Innate immunity · 2022Article
- Drug discovery and development scheme for liver-targeting bridged nucleic acid antisense oligonucleotides.Molecular therapy. Nucleic acids · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The identification of molecules that can modulate RNA or protein function and the subsequent chemical and structural optimization to refine such molecules into drugs is a key activity in drug discovery. Here, we explored the extent to which chemical and structural differences in antisense oligonucleotides, designed as gapmers and capable of recruiting RNase H for target RNA cleavage, can affect their functional properties. To facilitate structure-activity learning, we analyzed two sets of iso-sequential locked nucleic acid (LNA)-modified gapmers, where we systematically varied the number and positions of LNA modifications in the flanks. In total, we evaluated 768 different and architecturally diverse gapmers in HeLa cells for target knockdown activity and cytotoxic potential and found widespread differences in both of these properties. Binding affinity between gapmer and RNA target, as well as the presence of certain short sequence motifs in the gap region, can explain these differences, and we propose statistical and machine-learning models that can be used to predict region-specific, optimal LNA-modification architectures. Once accessible regions in the target of interest have been identified, our results show how to refine and optimize LNA gapmers with improved pharmacological profiles targeting such regions.
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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.