Comparison of the three large polymerase proteins of influenza A, B, and C viruses

Yamashita, Makoto; Krystal, Mark; Palese, Peter

doi:10.1016/0042-6822(89)90615-6

Cited by 68 publications

(61 citation statements)

References 24 publications

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“…The transcriptase is essential for virus replication in mammalian cells (27). It is highly conserved in influenza A and B viruses (40), and cap-depen-dent cleavage appears to be a unique property of influenza virus, having no known cellular counterpart. Only Bunyaviruses, also negative-strand, segmented RNA viruses, have been shown to possess a similar cap-dependent endonuclease activity.…”

mentioning

confidence: 99%

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Tomassini

Selnick

Davies

et al. 1994

Antimicrob Agents Chemother

180

188

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Synthesis of influenza virus mRNA is primed by capped and methylated (cap 1, m7GpppXm) RNAs which the virus derives by endonucleolytic cleavage from RNA polymerase II transcripts in host cells. The conserved nature of the endonucleolytic processing provides a unique target for the development of antiviral agents for influenza viruses. A series of 4-substituted 2,4-dioxobutanoic acid compounds has been identified as selective inhibitors of this activity in both influenza A and B viruses. These inhibitors exhibited 50%o inhibitory concentrations in the range of 0.2 to 29.0 ,uM for cap-dependent influenza virus transcription and had no effect on the activity of other viral and cellular polymerases when tested at 100-to 500-fold higher concentrations. The compounds did not inhibit the initiation or elongation of influenza virus mRNA synthesis but specifically inhibited the cleavage of capped RNAs by the influenza virus endonuclease and were not inhibitory to the activities of other nucleases. Additionally, the compounds specifically inhibited replication of influenza A and B viruses in cell culture with potencies comparable to the 50% inhibitory concentrations obtained for transcription.

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mentioning

confidence: 99%

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Tomassini

Selnick

Davies

et al. 1994

Antimicrob Agents Chemother

180

188

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“…Thus, type A, type B, and type C influenza viruses can be reliably classified. Sequencing has also proven that influenza type A, B, and C viruses have evolved from a common ancestor (18,30,31).…”

mentioning

confidence: 99%

Chimeric Influenza A Viruses with a Functional Influenza B Virus Neuraminidase or Hemagglutinin

Garcı́a-Sastre

Basler

et al. 2003

J Virol

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“…There is an overall low amino acid sequence similarity (approximately 36 to 38%) between the PA proteins of influenza A and B viruses (51,52). However, all five of the key catalytic-site residues necessary for enzymatic activity (H41, E80, D108, E119, and K134) are conserved (35).…”

Section: Discussionmentioning

confidence: 99%

The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses

Jones

Marathe

Vogel

et al. 2017

Antimicrob Agents Chemother

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Current influenza treatment relies on a single class of antiviral drugs, the neuraminidase inhibitors (NAIs), raising concern over the potential emergence of resistant variants and necessitating the development of novel drugs. In recent years, investigational inhibitors targeting the endonuclease activity of the influenza acidic polymerase (PA) protein have yielded encouraging results, although there are only limited data on their in vivo efficacy. Here, we examined the antiviral potential of the PA endonuclease inhibitor RO-7 in prophylactic and therapeutic regimens in BALB/c mice inoculated with influenza A/California/04/2009 (H1N1)pdm09 or B/Brisbane/60/2008 viruses, which represent currently circulating antigenic variants. RO-7 was administered to mice intraperitoneally twice daily at dosages of 6, 15, or 30 mg/ kg/day for 5 days, starting 4 h before or 24 or 48 h after virus inoculation, and showed no adverse effects. Prophylactic administration completely protected mice from lethal infection by influenza A or B virus. The level of therapeutic protection conferred depended upon the time of treatment initiation and RO-7 dosage, resulting in 60 to 100% and 80 to 100% survival with influenza A and B viruses, respectively. RO-7 treatment significantly decreased virus titers in the lung and lessened the extent and severity of lung damage. No PA endonuclease-inhibitor resistance was observed in viruses isolated from lungs of RO-7-treated mice, and the viruses remained susceptible to the drug at nanomolar concentrations in phenotypic assays. These in vivo efficacy results further highlight the potential of RO-7 for development as antiviral therapy for influenza A and B virus infections.

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Comparison of the three large polymerase proteins of influenza A, B, and C viruses

Cited by 68 publications

References 24 publications

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Chimeric Influenza A Viruses with a Functional Influenza B Virus Neuraminidase or Hemagglutinin

The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses

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