Synthetic oligoribonucleotides-containing secondary structures act as agonists of Toll-like receptors 7 and 8

Lan, Tao; Putta, Mallikarjuna Reddy; Wang, Daqing; Dai, Meiru; Yu, Dong; Kandimalla, Ekambar R.; Agrawal, Sudhir

doi:10.1016/j.bbrc.2009.06.036

Cited by 26 publications

(28 citation statements)

References 28 publications

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“…Our previous studies using transfected cell lines showed that the TLR7/8 agonist used herein activates both TLR7 and TLR8 (14)(15)(16)(17). In the present study, a TLR7/8 agonist induced potent immune and antitumor activities in TLR9 −/− , C57BL/6 WT, and BALB/c WT mice.…”

Section: Discussionsupporting

confidence: 66%

“…However, singlestranded RNA is highly susceptible to nuclease degradation, and the use of lipid carriers has been required to stabilize RNAs against nucleases (12,(31)(32)(33)(34)(35)(36). We have designed RNAs linked through their 3′-ends to prevent 3′-exonuclease degradation, referred to as SIMRA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8, depending on the nucleotide sequence and chemical modifications incorporated (14)(15)(16)(17). SIMRA compounds induce Th1-type immune responses without lipid formulation in vitro and in vivo, including in nonhuman primates (14).…”

Section: Discussionmentioning

confidence: 99%

“…Synthesis and purification of oligoribonucleotidebased dual TLR7/8 agonist, 5′-UG1CUG1CUUCUG1-X-G1UCUUCG1UCG1U-5′, wherein G1 and X represent 7-deazaguanosine and 1,2,3-propanetriol linker, respectively, were carried out as described previously (14,15). The TLR7/8 agonist was synthesized with phosphorothioate backbone modification.…”

Section: Reagentsmentioning

confidence: 99%

“…Wide use of synthetic RNA as agonists of TLR7 and TLR8 has been hampered by their susceptibility to nuclease degradation (10)(11)(12), and lipid carriers have been needed for in vitro and in vivo studies (8,(11)(12)(13). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immune-modulatory RNA (SIMRA) compounds (14)(15)(16)(17). We have shown that SIMRA compounds act as TLR7, TLR8, and dual TLR7/8 agonists, depending on the sequence composition and specific chemical modifications present in them (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…We have shown that SIMRA compounds act as TLR7, TLR8, and dual TLR7/8 agonists, depending on the sequence composition and specific chemical modifications present in them (14)(15)(16)(17). SIMRA compounds induce potent immune responses in cellbased assays and in vivo in mice and nonhuman primates without requiring formulation with lipid carriers (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Wang

Precopio

Lan

et al. 2010

Molecular Cancer Therapeutics

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Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immunemodulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4 + CD25 + Foxp3 + T regulatory cells and a significant increase in tumor antigen-specific IFN-γ-secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9 −/− mice, but not in TLR7 −/− and MyD88 −/− mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway. Mol Cancer Ther; 9(6); 1788-97. ©2010 AACR.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Wang

Precopio

Lan

et al. 2010

Molecular Cancer Therapeutics

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An RNA Interference/Adeno‐Associated Virus Vector–Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus

et al. 2021

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Hepatitis E virus (HEV) is a major public health problem with limited therapeutic options. Here, we engineered adeno‐associated viral vectors of serotype 6 (AAV6) to express short hairpin RNAs (shRNAs) against HEV transcripts with the prospect of down‐regulating HEV replication in vivo. We designed 20 different shRNAs, targeting the genome of the HEV genotype 3 (GT3) Kernow‐C1 p6 strain, for delivery upon AAV6 transduction. Using an original selectable HEV GT3 reporter replicon, we identified three shRNAs that efficiently down‐regulated HEV replication. We further confirmed their inhibitory potency with full‐length HEV infection. Seventy‐two hours following transduction, HEV replication in both systems decreased by up to 95%. The three most potent inhibitory shRNAs identified were directed against the methyltransferase domain, the junction region between the open reading frames (ORFs), and the 3´ end of ORF2. Targeting all three regions by multiplexing the shRNAs further enhanced their inhibitory potency over a prolonged period of up to 21 days following transduction. Conclusion: Combining RNA interference and AAV vector–based gene therapy has great potential for suppressing HEV replication. Our strategy to target the viral RNA with multiplexed shRNAs should help to counteract viral escape through mutations. Considering the widely documented safety of AAV vector–based gene therapies, our approach is, in principle, amenable to clinical translation.

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Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

Kandimalla

Agrawal

2011

Nucleic Acid Drugs

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Synthetic oligoribonucleotides-containing secondary structures act as agonists of Toll-like receptors 7 and 8

Cited by 26 publications

References 28 publications

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8

An RNA Interference/Adeno‐Associated Virus Vector–Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus

Modulation of Endosomal Toll-Like Receptor-Mediated Immune Responses by Synthetic Oligonucleotides

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