Current and novel antiviral strategies for influenza infection

Yen, Hui-Ling

doi:10.1016/j.coviro.2016.05.004

Cited by 50 publications

(45 citation statements)

References 99 publications

(94 reference statements)

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“…The PB1 protein-targeted drug T-705 has been approved for limited-use influenza therapy (in pandemic scenarios) in Japan for over 2 years (12,34), and phase III clinical trials in the United States have recently been completed (55). Phase II clinical trials are under way with the cap-binding influenza PB2 protein inhibitor VX-787/JNJ872 and include combination therapy with NAI OSE.…”

Section: Discussionmentioning

confidence: 99%

“…The NAIs (oseltamivir, zanamivir, peramivir, and laninamivir) inhibit NA enzymatic activity that is necessary for virus release from host cells (12). The development of NAI resistance is of critical concern.…”

mentioning

confidence: 99%

“…The incidence of NAI resistance among seasonal influenza viruses remains low (0.1 to 3%) (15,16). However, NAI resistance-associated substitutions have been identified in the clinic in patients infected with H1N1pdm09, H3N2, and H5N1 viruses (12,17). Influenza B viruses are less susceptible to NAIs in phenotypic enzyme-inhibition assays (12), and although no clinical studies have exclusively analyzed NAI efficacy against infection with influenza B virus alone, meta-analysis of aggregated data suggests that NAIs may be less efficacious against influenza B than against influenza A virus (12,17,18).…”

mentioning

confidence: 99%

“…However, NAI resistance-associated substitutions have been identified in the clinic in patients infected with H1N1pdm09, H3N2, and H5N1 viruses (12,17). Influenza B viruses are less susceptible to NAIs in phenotypic enzyme-inhibition assays (12), and although no clinical studies have exclusively analyzed NAI efficacy against infection with influenza B virus alone, meta-analysis of aggregated data suggests that NAIs may be less efficacious against influenza B than against influenza A virus (12,17,18). Furthermore, NAIs generally have a narrow treatment window (requiring initiation of treatment within 48 h of symptom onset) and may have less desirable routes of administration (i.e., inhalation, in the case of zanamivir and laninamivir) (10,11,19).…”

mentioning

confidence: 99%

“…Experimental inhibitors have been described that affect PB2 capbinding activity (PB2-39 [26], BPR3P0128 [27], Cap-3/7 [28], RO and PPT28 [29]) or that disrupt the interaction of PB2 with the polymerase complex (PB1 731-757 peptide [30] and PB2 1-37 peptide [31]). One PB2 inhibitor (VX-787/JNJ872) is currently undergoing phase 2b clinical trials (12,(32)(33)(34). The PA protein contains the endonuclease activity required to cleave PB2-bound capped mRNAs and initiate viral transcription (35).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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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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Ultrasensitive Fluorogenic Reagents for Neuraminidase Titration

2017

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Influenza viral neuraminidase playsacrucial role during infections.I ti samajor target for the development of anti-influenza drugs and is also attracting increasing attention as av accine target as evidence accumulates that neuraminidase-neutralizing antibodies contribute to protection. However,n om ethod currently exists to accurately and efficiently measure concentrations of active neuraminidase in virus samples or other crude mixtures,which hampers development on both fronts.I nt his report, we describe the development of as elective and sensitive active-site titration reagent for neuraminidase that can quantify viral neuraminidases down to sub-nanomolar levels in crude samples,with no background from non-viral neuraminidases.B yu sing this reagent, we determined accurate k cat values for six influenza Aa nd two influenza Bn euraminidases for the first time.W ea lso quantified the neuraminidase content in ac ommercial influenza vaccine,thus demonstrating that this titration reagent opens the possibility for better vaccine analysis.

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Ultrasensitive Fluorogenic Reagents for Neuraminidase Titration

2017

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Influenza viral neuraminidase plays a crucial role during infections. It is a major target for the development of anti-influenza drugs and is also attracting increasing attention as a vaccine target as evidence accumulates that neuraminidase-neutralizing antibodies contribute to protection. However, no method currently exists to accurately and efficiently measure concentrations of active neuraminidase in virus samples or other crude mixtures, which hampers development on both fronts. In this report, we describe the development of a selective and sensitive active-site titration reagent for neuraminidase that can quantify viral neuraminidases down to sub-nanomolar levels in crude samples, with no background from non-viral neuraminidases. By using this reagent, we determined accurate k values for six influenza A and two influenza B neuraminidases for the first time. We also quantified the neuraminidase content in a commercial influenza vaccine, thus demonstrating that this titration reagent opens the possibility for better vaccine analysis.

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Current and novel antiviral strategies for influenza infection

Cited by 50 publications

References 99 publications

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

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

Ultrasensitive Fluorogenic Reagents for Neuraminidase Titration

Ultrasensitive Fluorogenic Reagents for Neuraminidase Titration

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