ArticleBioorganic & medicinal chemistry2018
TLR8 activation and inhibition by guanosine analogs in RNA: Importance of functional groups and chain length.
Article in Bioorganic & medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- TLR8 gain-of-function syndrome.Journal of human immunity · 2026Article
- 1-Deazainosine-impact on RNA structure and role in exploring ribozyme catalysis.Chemical science · 2026Article
- Engineering polymeric RNA scaffolds as programmable combinatorial innate immune agonists.Nucleic acids research · 2026Article
- Article
- Nucleotide metabolism: a pan-cancer metabolic dependency.Nature reviews. Cancer · 2023Review
- 1-Deazaguanosine-Modified RNA: The Missing Piece for Functional RNA Atomic Mutagenesis.Journal of the American Chemical Society · 2022Article
- Activation of Innate Immunity by Therapeutic Nucleic Acids.International journal of molecular sciences · 2021Review
- Impact of 3-deazapurine nucleobases on RNA properties.Nucleic acids research · 2021Article
- Inhibitory Effects of DietaryFrontiers in immunology · 2020Article
- Investigation of 8-Aza-7-Deaza Purine Nucleoside Derivatives.Molecules (Basel, Switzerland) · 2019Article
- Nucleoside analogs in the study of the epitranscriptome.Methods (San Diego, Calif.) · 2019Review
- Review
- Small-Molecule TLR8 Antagonists via Structure-Based Rational Design.Cell chemical biology · 2018Article
- Double methylation of tRNA-U54 to 2'-O-methylthymidine (Tm) synergistically decreases immune response by Toll-like receptor 7.Nucleic acids research · 2018Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Toll-like receptor 8 (TLR8) is an important component of the human innate immune system that recognizes single stranded RNA (ssRNA). Recent X-ray crystal structures of TLR8 bound to ssRNA revealed a previously unrecognized binding site for a 5'-UpG-3' dinucleotide. Here we use an atomic mutagenesis strategy coupled with a cellular TLR8 activation assay to probe the importance of specific functional groups present on the guanine base in RNA-mediated receptor agonism and antagonism. Results from RNA analogs containing 7-deazaguanosine, 2-aminopurine and inosine confirm the importance of guanine N7, O6 and N2, respectively, in TLR8 activation. Nevertheless, these RNAs each retained TLR8 antagonism activity. RNA containing 7-deaza-8-azainosine (7d8aI) was prepared from a novel phosphoramidite and found to be a weaker TLR8 activator than guanosine-containing RNA. However, 7d8aI-containing RNA also retained TLR8 antagonism activity indicating that removal of multiple TLR8 H-bonding sites on guanine is insufficient for blocking TLR8 antagonism by guanine-containing RNA. We also identified an oligoribonucleotide length dependence on both TLR8 activation and antagonism. These studies extend our understanding of the effects of nucleobase modification on immune stimulation and will inform the design of novel RNA-based therapeutics.
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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.