Inhibitory Effects of an Antisense Oligonucleotide in an Experimentally Infected Mouse Model of Influenza A Virus

Mizuta, Tadashi; Fujiwara, Masatoshi; Abe, Takayuki; Miyano-Kurosaki, Naoko; Yokota, Tomoyuki; Shigeta, Shirô; Takaku, Hiroshi

doi:10.1006/bbrc.2000.3924

Cited by 19 publications

(11 citation statements)

References 22 publications

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“…DNAzymes (46), oligoaptamers (45), and short interfering RNA (10,12) have all been documented to have antiviral activity in cell culture, and short interfering RNA has been documented to have antiviral activity in mice (11,47), against FLUAV. Intravenous delivery in mice of a liposome-encapsulated antisense phosphorothioate oligonucleotide with sequence complementary to the translation start site region of PB2 mRNA reduced FLUAV titers in lung tissue and significantly increased overall survival rates (26,27). To ultimately achieve clinical utility, any nucleic acid-based anti-FLUAV therapeutic will need to possess a number of favorable pharmacologic qualities, including in vivo stability, low toxicity, and the ability to reach viral RNA targets within relevant cell populations.…”

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confidence: 99%

Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers

Pastey

Kobasa

et al. 2006

Antimicrob Agents Chemother

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Peptide-conjugated phosphorodiamidate morpholino oligomers (P-PMO) are single-stranded nucleic acid-like antisense agents that can reduce gene expression by sterically blocking complementary RNA sequence. P-PMO are water soluble and nuclease resistant, and they readily achieve uptake into cells in culture under standard conditions. Eight P-PMO, each 20 to 22 bases in length, were evaluated for their ability to inhibit influenza A virus (FLUAV) A/PR/8/34 (H1N1) replication in cell culture. The P-PMO were designed to base pair with FLUAV RNA sequences that are highly conserved across viral subtypes and considered critical to the FLUAV biological-cycle, such as gene segment termini and mRNA translation start site regions. Several P-PMO were highly efficacious, each reducing viral titer in a dose-responsive and sequence-specific manner in A/PR/8/34-infected cells. Two P-PMO, one designed to target the AUG translation start site region of PB1 mRNA and the other the 3-terminal region of nucleoprotein viral genome RNA, also proved to be potent against several other FLUAV strains, including A/WSN/33 (H1N1), A/Memphis/8/88 (H3N2), A/Eq/Miami/63 (H3N8), A/Eq/Prague/56 (H7N7), and the highly pathogenic A/Thailand/1(KAN-1)/04 (H5N1). The P-PMO exhibited minimal cytotoxicity in cell viability assays. High efficacy by two of the P-PMO against multiple FLUAV subtypes suggests that these oligomers represent a broad-spectrum therapeutic approach against a high percentage of known FLUAV strains.

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confidence: 99%

Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers

Pastey

Kobasa

et al. 2006

Antimicrob Agents Chemother

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“…1 ). We previously reported that antisense phosphorothioate oligonucleotides targeting the AUG initiation codon sequences of PB2 mRNA effectively inhibited the influenza virus RNA polymerase activity and influenza virus replication in infected cells [36,37] and mice [5,38]. For comparison with the active DNA enzyme, we also designed inactive DNA enzymes, PB2Dz‐9‐I, PB2Dz‐9‐IN, and PB2Dz‐9‐IN(*2) (same arm sequences as PB2Dz‐9, PB2Dz‐9‐N, and PB2Dz‐9‐N(*2) with an inverted catalytic core sequence) [24].…”

Section: Resultsmentioning

confidence: 99%

“…Comparisons of the kinetic parameters revealed no significant differences in the K cat / K M values between the unmodified and modified DNA enzymes (Table 1). From the above results, we selected the modified DNA enzymes [PB2Dz‐9‐N and PB2Dz‐9‐N(*2), and PB2Dz‐9‐M(*2)], with higher cleavage activity and nuclease resistance, for the subsequent anti‐influenza activity studies [38]. As the control oligonucleotides, we used the inactive DNA enzymes with inverted catalytic domains [PB2Dz‐9‐IN, PB2Dz‐9‐IN(*2), and PB2Dz‐9‐IM(*2)] and the antisense oligonucleotide (PB2‐as‐N) with one N3′‐P5′ phosphoramidate modification at both the 3′‐ and 5′‐ends.…”

Section: Discussionmentioning

confidence: 99%

A new modified DNA enzyme that targets influenza virus A mRNA inhibits viral infection in cultured cells

et al. 2004

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DNA enzymes are RNA-cleaving single-stranded DNA molecules. We designed DNA enzymes targeting the PB2 mRNA translation initiation (AUG) region of the in£uenza A virus (A/PR/8/34). The modi¢ed DNA enzymes have one or two N3P P-P5P P phosphoramidate bonds at both the 3P P-and 5P Ptermini of the oligonucleotides, which signi¢cantly enhanced their nuclease resistance. These modi¢ed DNA enzymes had the same cleavage activity as the unmodi¢ed DNA enzymes, determined by kinetic analyses, and reduced in£uenza A virus replication by more than 99%, determined by plaque formation. These DNA enzymes are highly speci¢c; their protective e¡ect was not observed in in£uenza B virus (B/Ibaraki)-infected Madin^Darby canine kidney cells.

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“…This class of agents has promising antiviral activities, as shown in animal studies 8. The use of ASOs against influenza virus infections has been reported in tissue culture and animal infection models by targeting the PA, PB1, PB2, NP, NS1 and HA genes of influenza A, including H1N1 and H5N1 strains 9, 10. It is worth noting that there have been no reports on the use of ASOs targeting PB2 that could improve the survival of H5N1‐infected mice.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of highly pathogenic avian H5N1 influenza virus propagation by RNA oligonucleotides targeting the PB2 gene in combination with celecoxib

Jin¹,

Zhang²,

Hu³

et al. 2011

The Journal of Gene Medicine

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Inhibitory Effects of an Antisense Oligonucleotide in an Experimentally Infected Mouse Model of Influenza A Virus

Cited by 19 publications

References 22 publications

Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers

Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers

A new modified DNA enzyme that targets influenza virus A mRNA inhibits viral infection in cultured cells

Inhibition of highly pathogenic avian H5N1 influenza virus propagation by RNA oligonucleotides targeting the PB2 gene in combination with celecoxib

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