Abstract:
:Anti-microRNA (miRNA) oligonucleotides (AMOs) with 2'-O-Methyl (2'OMe) residues are commonly used to study miRNA function and can achieve high potency, with low cytotoxicity. Not withstanding this, we demonstrate the sequence-dependent capacity of 2'OMe AMOs to inhibit Toll-like receptor (TLR) 7 and 8 sensing of immunostimulatory RNA, independent of their miRNA-targeting function. Through a screen of 29 AMOs targeting common miRNAs, we found a subset of sequences highly inhibitory to TLR7 sensing in mouse macrophages. Interspecies conservation of this inhibitory activity was confirmed on TLR7/8 activity in human peripheral blood mononuclear cells. Significantly, we identified a core motif governing the inhibitory activity of these AMOs, which is present in more than 50 AMOs targeted to human miRNAs in miRBaseV20. DNA/locked nucleic acids (LNA) AMOs synthesized with a phosphorothioate backbone also inhibited TLR7 sensing in a sequence-dependent manner, demonstrating that the off-target effects of AMOs are not restricted to 2'OMe modification. Taken together, our work establishes the potential for off-target effects of AMOs on TLR7/8 function, which should be taken into account in their therapeutic development and in vivo application.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Sarvestani ST,Stunden HJ,Behlke MA,Forster SC,McCoy CE,Tate MD,Ferrand J,Lennox KA,Latz E,Williams BR,Gantier MPdoi
10.1093/nar/gku1343subject
Has Abstractpub_date
2015-01-01 00:00:00pages
1177-88issue
2eissn
0305-1048issn
1362-4962pii
gku1343journal_volume
43pub_type
杂志文章abstract::The circular dichroism spectra of Hg(II) complexes with native calf thymus DNA, chemically methylated Streptomyces chrysomallus DNA and with Ag(I)-DNA complexes were measured in the region of 220 - 340 nm. As a main result a conversion of the conservative CD spectrum of DNA to a distinct nonconservative type of CD spe...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/4.3.539
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abstract::A simplified and economical method for the attachment of 2'-deoxyribo, ribo and arabinonucleosides onto long-chain alkylamidopropanoic acid controlled-pore glass (LCAAP-CPG, P-3) is described. In this procedure, 5'-O-tritylated nucleosides are coupled directly to LCAAP-CPG in excellent yields using 1-(3-dimethylaminop...
journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
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更新日期:2011-08-01 00:00:00
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
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更新日期:2019-01-10 00:00:00
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journal_title:Nucleic acids research
pub_type: 杂志文章
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