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- W2274663911 endingPage "e0128686" @default.
- W2274663911 startingPage "e0128686" @default.
- W2274663911 abstract "The inhibitory potency of an antisense oligonucleotide depends critically on its design and the accessibility of its target site. Here, we used an RNA interference-guided approach to select antisense oligonucleotide target sites in the coding region of the highly structured hepatitis C virus (HCV) RNA genome. We modified the conventional design of an antisense oligonucleotide containing locked nucleic acid (LNA) residues at its termini (LNA/DNA gapmer) by inserting 8-oxo-2'-deoxyguanosine (8-oxo-dG) residues into the central DNA region. Obtained compounds, designed with the aim to analyze the effects of 8-oxo-dG modifications on the antisense oligonucleotides, displayed a unique set of properties. Compared to conventional LNA/DNA gapmers, the melting temperatures of the duplexes formed by modified LNA/DNA gapmers and DNA or RNA targets were reduced by approximately 1.6-3.3°C per modification. Comparative transfection studies showed that small interfering RNA was the most potent HCV RNA replication inhibitor (effective concentration 50 (EC50): 0.13 nM), whereas isosequential standard and modified LNA/DNA gapmers were approximately 50-fold less efficient (EC50: 5.5 and 7.1 nM, respectively). However, the presence of 8-oxo-dG residues led to a more complete suppression of HCV replication in transfected cells. These modifications did not affect the efficiency of RNase H cleavage of antisense oligonucleotide:RNA duplexes but did alter specificity, triggering the appearance of multiple cleavage products. Moreover, the incorporation of 8-oxo-dG residues increased the stability of antisense oligonucleotides of different configurations in human serum." @default.
- W2274663911 created "2016-06-24" @default.
- W2274663911 creator A5002518848 @default.
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- W2274663911 date "2015-06-03" @default.
- W2274663911 modified "2023-10-14" @default.
- W2274663911 title "RNA Interference-Guided Targeting of Hepatitis C Virus Replication with Antisense Locked Nucleic Acid-Based Oligonucleotides Containing 8-oxo-dG Modifications" @default.
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- W2274663911 doi "https://doi.org/10.1371/journal.pone.0128686" @default.
- W2274663911 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4454572" @default.
- W2274663911 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26039055" @default.
- W2274663911 hasPublicationYear "2015" @default.