A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus Activity
            <i>In Vitro</i>

Jones, Jeremy C.; Marathe, Bindumadhav M.; Lerner, C.; Kreis, Lukas M.; Gasser, Rodolfo; Pascua, Philippe Noriel Q.; Nájera, Isabel; Govorkova, Elena A.

doi:10.1128/aac.00888-16

Cited by 46 publications

(43 citation statements)

References 74 publications

(82 reference statements)

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“…To study respiratory infections, traditionally cell lines and undifferentiated monolayer epithelial cells in submerged cultures were used, which couldn't replicate faithfully the real mechanisms of viral infections in human respiratory tract. Therefore, increasing number of studies turned recently toward ALI models, because of its high physiological and functional relevance, to investigate certain aspects of the respiratory viral infections (Berman et al, 2016;Farsani et al, 2015;Griggs et al, 2017;Jones et al, 2016). In this study, we undertook a rather holistic analysis of the physiological modifications happening in a human 3D airway ALI culture upon viral infection and revealed the importance of an innate immune response which is virus strain dependent.…”

Section: Discussionmentioning

confidence: 97%

“…Overall, our data support the use of the standardized MucilAir™ airway as a promising preclinical model for the design and the test of novel antiviral strategies. In comparison with other air-liquid interface 3D approaches (Berman et al, 2016;Farsani et al, 2015;Griggs et al, 2017;Jones et al, 2016), MucilAir™ is made of low passage human airway epithelial cells ensuring a maximum similarity with physiological condition and the reconstruction is standardized with quality control using functional tests. Some important assets of MucilAir™ for pre-clinical testing have already been addressed.…”

Section: Discussionmentioning

confidence: 99%

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Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

et al. 2018

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Respiratory viral infections cause mild to severe diseases, such as common cold, bronchiolitis and pneumonia and are associated with substantial burden for society. To test new molecules for shortening, alleviating the diseases or to develop new therapies, relevant human in vitro models are mandatory. MucilAir™, a human standardized air-liquid interface 3D airway epithelial culture holds in vitro specific mechanisms to counter invaders comparable to the in vivo situation, such as mucus production, mucociliary clearance, and secretion of defensive molecules. The objective of this study was to test the relevance of such a model for the discovery and validation of antiviral drugs. Fully differentiated 3D nasal epithelium cultures were inoculated with picornaviruses, a coronavirus and influenza A viruses in the absence or in the presence of reference antiviral drugs. Results showed that, rupintrivir efficiently inhibits the replication of respiratory picornaviruses in a dose dependent manner and prevents the impairment of the mucociliary clearance. Similarly, oseltamivir reduced the replication of influenza A viruses in a dose dependent manner and prevented the impairment of the epithelial barrier function and cytotoxicity until 4 days of infection. In addition we found that Rhinovirus B14, C15 and influenza A(H1N1) induce significant increase of β Defensins 2 and Cathelicidin release with different time course. These results reveal that a large panel of epithelial functions is modified upon viral infection and validate MucilAir™ as a pertinent tool for pre-clinical antiviral drug testing.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

et al. 2018

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“…However, all five of the key catalytic-site residues necessary for enzymatic activity (H41, E80, D108, E119, and K134) are conserved (35). It is therefore not surprising that RO-7, along with other PA endonuclease inhibitors, showed activity against both influenza A and B viruses in vitro (39) and, as we have now demonstrated, in vivo. The broad-spectrum activity of RO-7 and other endonuclease inhibitors against influenza A and B viruses also makes them more advantageous than the current cap-binding PB2 polymerase inhibitors, which are capable of inhibiting infections by influenza A viruses only (33,34).…”

Section: Discussionmentioning

confidence: 64%

“…1A), a small-molecule, broad-spectrum inhibitor of the influenza A and B virus PA endonuclease protein (39). In vitro, RO-7 was effective at nanomolar 50% effective concentrations (EC 50 ) in MDCK cells (3.2 to 16.0 nM) and in differentiated normal human bronchial epithelial cells (3 and 30 nM).…”

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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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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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The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide

Tilmanis

Baalen

et al. 2017

Antiviral Research

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Nitazoxanide is a thiazolide compound that was originally developed as an anti-parasitic agent, but has recently been repurposed for the treatment of influenza virus infections. Thought to exert its anti-influenza activity via the inhibition of hemagglutinin maturation and intracellular trafficking in infected cells, the effectiveness of nitazoxanide in treating patients with non-complicated influenza is currently being assessed in phase III clinical trials. Here, we describe the susceptibility of 210 seasonal influenza viruses to tizoxanide, the active circulating metabolite of nitazoxanide. An optimised cell culture-based focus reduction assay was used to determine the susceptibility of A(H1N1)pdm09, A(H3N2), and influenza B viruses circulating in the southern hemisphere from the period March 2014 to August 2016. Tizoxanide showed potent in vitro antiviral activity against all influenza viruses tested, including neuraminidase inhibitor-resistant viruses, allowing the establishment of a baseline level of susceptibility for each subtype. Median EC values (±IQR) of 0.48 μM (0.33-0.71), 0.62 μM (0.56-0.75), 0.66 μM (0.62-0.69), and 0.60 μM (0.51-0.67) were obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses respectively. There was no significant difference in the median baseline tizoxanide susceptibility for each influenza subtype tested. This is the first report on the susceptibility of circulating viruses to tizoxanide. The focus reduction assay format described is sensitive, robust, and less laborious than traditional cell based antiviral assays, making it highly suitable for the surveillance of tizoxanide susceptibility in circulating seasonal influenza viruses.

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A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus Activity In Vitro

Cited by 46 publications

References 74 publications

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

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

The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide

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