ArticleNucleic acids research2020
Rational design of antisense oligonucleotides modulating the activity of TLR7/8 agonists.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 34 citations in OpenAlex.
- Beyond inflammation: siRNA strategies for precision targeting in rheumatological disorders.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- 2'-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity.Nature immunology · 2026Article
- Functional characterization of dynamic nascent RNA folding ensembles in real time.Science advances · 2026Article
- [Clinical research advances for small-molecule nucleic acid drugs in the treatment of chronic hepatitis B].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025Review
- Circular single stranded DNA potentiates non-viral gene insertion in hematopoietic stem and progenitor cells.Nature communications · 2025Article
- Targeting pattern recognition receptors for cancer therapy: Mechanisms and strategies.Acta pharmaceutica Sinica. B · 2025Review
- Trends and Commonalities of Approved and Late Clinical-Phase RNA Therapeutics.Pharmaceutics · 2025Review
- Evolution of antisense oligonucleotides: navigating nucleic acid chemistry and delivery challenges.Expert opinion on drug discovery · 2025Review
- Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review.International journal of molecular sciences · 2024Review
- Nucleotide modifications enable rational design of TLR7-selective ligands by blocking RNase cleavage.The Journal of experimental medicine · 2024Article
- Characterization of cooperative PS-oligo activation of human TLR9.Molecular therapy. Nucleic acids · 2023Article
- The influence of chirality on the behavior of oligonucleotides inside cells: revealing the potent cytotoxicity of G-rich l-RNA.Chemical science · 2023Article
- Selecting Therapeutic Antisense Oligonucleotides with Gene Targeting and TLR8 Potentiating Bifunctionality.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.Nucleic acid therapeutics · 2023Review
- Insights into innate immune activation via PS-ASO-protein-TLR9 interactions.Nucleic acids research · 2022Article
- MicroRNAs as therapeutic targets in cardiovascular disease.The Journal of clinical investigation · 2022Review
- Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.NPJ genomic medicine · 2022Article
- A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway.Frontiers in microbiology · 2022Article
- Sterilizing Immunity against COVID-19: Developing Helper T cells I and II activating vaccines is imperative.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2021Review
- Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists.Nature communications · 2021Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oligonucleotide-based therapeutics have become a reality, and are set to transform management of many diseases. Nevertheless, the modulatory activities of these molecules on immune responses remain incompletely defined. Here, we show that gene targeting 2'-O-methyl (2'OMe) gapmer antisense oligonucleotides (ASOs) can have opposing activities on Toll-Like Receptors 7 and 8 (TLR7/8), leading to divergent suppression of TLR7 and activation of TLR8, in a sequence-dependent manner. Surprisingly, TLR8 potentiation by the gapmer ASOs was blunted by locked nucleic acid (LNA) and 2'-methoxyethyl (2'MOE) modifications. Through a screen of 192 2'OMe ASOs and sequence mutants, we characterized the structural and sequence determinants of these activities. Importantly, we identified core motifs preventing the immunosuppressive activities of 2'OMe ASOs on TLR7. Based on these observations, we designed oligonucleotides strongly potentiating TLR8 sensing of Resiquimod, which preserve TLR7 function, and promote strong activation of phagocytes and immune cells. We also provide proof-of-principle data that gene-targeting ASOs can be selected to synergize with TLR8 agonists currently under investigation as immunotherapies, and show that rational ASO selection can be used to prevent unintended immune suppression of TLR7. Taken together, our work characterizes the immumodulatory effects of ASOs to advance their therapeutic development.
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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.