ArticleProceedings of the National Academy of Sciences of the United States of America2003
A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 60 citations in OpenAlex.
- Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703.Nucleic acid therapeutics · 2015Article
- Novel drugs targeting Toll-like receptors for antiviral therapy.Future virology · 2014Article
- Immune-Stimulatory Dinucleotide at the 5'-End of Oligodeoxynucleotides Is Critical for TLR9-Mediated Immune Responses.ACS medicinal chemistry letters · 2013Article
- An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy.PloS one · 2012Article
- Immunomodulatory Agents with Antivascular Activity in the Treatment of Non-Small Cell Lung Cancer: Focus on TLR9 Agonists, IMiDs and NGR-TNF.Journal of oncology · 2010Article
- Coadministration of telomerase genetic vaccine and a novel TLR9 agonist in nonhuman primates.Molecular therapy : the journal of the American Society of Gene Therapy · 2009Article
- Impact of secondary structure of toll-like receptor 9 agonists on interferon alpha induction.Antimicrobial agents and chemotherapy · 2008Article
- Immune modulatory oligonucleotides in the prevention and treatment of allergen-induced eustachian tube dysfunction in the animal model.Current allergy and asthma reports · 2008Review
- Broad-spectrum drugs against viral agents.International journal of molecular sciences · 2008Article
- Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8.Proceedings of the National Academy of Sciences of the United States of America · 2007Article
- TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts.Proceedings of the National Academy of Sciences of the United States of America · 2007Article
- Novel oligodeoxynucleotide agonists of TLR9 containing N3-Me-dC or N1-Me-dG modifications.Nucleic acids research · 2006Article
- Immunomodulatory oligonucleotides containing a cytosine-phosphate-2'-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists.Proceedings of the National Academy of Sciences of the United States of America · 2005Article
- CpG ODNs treatments of HIV-1 infected patients may cause the decline of transmission in high risk populations - a review, hypothesis and implications.Virus genes · 2005Review
- Immune stimulating properties of a novel polysaccharide from the medicinal plant Tinospora cordifolia.International immunopharmacology · 2004Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bacterial and synthetic DNAs containing CpG dinucleotides in specific sequence contexts activate the vertebrate immune system through Toll-like receptor 9 (TLR9). In the present study, we used a synthetic nucleoside with a bicyclic heterobase [1-(2'-deoxy-beta-d-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine; R] to replace the C in CpG, resulting in an RpG dinucleotide. The RpG dinucleotide was incorporated in mouse- and human-specific motifs in oligodeoxynucleotides (oligos) and 3'-3-linked oligos, referred to as immunomers. Oligos containing the RpG motif induced cytokine secretion in mouse spleen-cell cultures. Immunomers containing RpG dinucleotides showed activity in transfected-HEK293 cells stably expressing mouse TLR9, suggesting direct involvement of TLR9 in the recognition of RpG motif. In J774 macrophages, RpG motifs activated NF-kappa B and mitogen-activated protein kinase pathways. Immunomers containing the RpG dinucleotide induced high levels of IL-12 and IFN-gamma, but lower IL-6 in time- and concentration-dependent fashion in mouse spleen-cell cultures costimulated with IL-2. Importantly, immunomers containing GTRGTT and GARGTT motifs were recognized to a similar extent by both mouse and human immune systems. Additionally, both mouse- and human-specific RpG immunomers potently stimulated proliferation of peripheral blood mononuclear cells obtained from diverse vertebrate species, including monkey, pig, horse, sheep, goat, rat, and chicken. An immunomer containing GTRGTT motif prevented conalbumin-induced and ragweed allergen-induced allergic inflammation in mice. We show that a synthetic bicyclic nucleotide is recognized in the C position of a CpG dinucleotide by immune cells from diverse vertebrate species without bias for flanking sequences, suggesting a divergent nucleotide motif recognition pattern of TLR9.
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