Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection

Mendel, Dirk B.; Tai, Chun Y.; Escarpe, Paul A.; Li, Weixing; Sidwell, Robert W.; Huffman, John H.; Sweet, C.; Jakeman, K. J.; Merson, James; Lacy, Steven; Lew, Willard; Williams, Matthew A.; Zhang, Lijun; Chen, Ming S.; Bischofberger, Norbert; Kim, Choung U.

doi:10.1128/aac.42.3.640

Cited by 242 publications

(126 citation statements)

References 40 publications

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“…Significantly better antiviral efficacy could be demonstrated in direct comparison to amantadine and rimantadine. The results of this study correlate with in vivo trials in which oseltamivir and zanamivir have proven to prevent death after influenza A virus infection in mice [15,21]. However, the minimum effective dosages in mice were considerably lower than in eggs.…”

Section: Discussionsupporting

confidence: 77%

Utilization of the embryonated egg for in vivo evaluation of the anti-influenza virus activity of neuraminidase inhibitors

Sauerbrei

Haertl

Brandstaedt

et al. 2005

Med Microbiol Immunol

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Previous studies have shown that embryonated egg provides a convenient and easy to use system for in vivo screening of anti-influenza virus inhibitors. However, it is not known whether this model is suitable for testing neuraminidase (NA) inhibitors, too. Therefore, the present study describes the evaluation of the ion-channel blockers amantadine and rimantadine in comparison with the NA inhibitors oseltamivir and zanamivir by using the influenza A virus hen's egg model. The treatment was started immediately before or after the challenge dose was placed on the chorioallantoic membrane (CAM). Differences between the survival rate of treated and untreated chick embryos infected with influenza A virus were analyzed statistically. As result, the survival rate of chick embryos could be significantly increased when the treatment with amantadine, rimantadine, oseltamivir, or zanamivir was started before the CAM was inoculated with one egg infective dose 50% (EID50) influenza A virus. When the drugs were administered shortly after viral inoculation, significant antiviral efficacy was shown for rimantadine, oseltamivir, and zanamivir. Antiviral efficacy could be demonstrated exclusively for both oseltamivir and zanamivir after the embryos were infected with higher challenge doses of 10(2) EID50 influenza A virus. In conclusion, the NA inhibitors oseltamivir and zanamivir have a significantly better antiviral activity against influenza A virus than amantadine and rimantadine tested in embryonated hen's eggs. Therefore, this model can be a valuable alternative approach for in vivo pre-testing anti-influenza virus activity of NA inhibitors.

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Section: Discussionsupporting

confidence: 77%

Utilization of the embryonated egg for in vivo evaluation of the anti-influenza virus activity of neuraminidase inhibitors

Sauerbrei

Haertl

Brandstaedt

et al. 2005

Med Microbiol Immunol

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“…Tamiflu is the ethyl ester pro-drug of the anti- influenza drug oseltamivir carboxylate, which is converted to this biologically active form in vivo [19]. Since Tamiflu is known to be ineffective in vitro because its antiviral activity is achieved by its hydrolytic metabolite oseltamivir carboxylate [20], we have actually observed the opposite effect in our live cell assay system.…”

Section: Sialidase Activity Associated With Tlr Ligand Treated Live Pmentioning

confidence: 76%

Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase

et al. 2009

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The signaling pathways of mammalian Toll-like receptors (TLR) are well characterized, but the initial molecular mechanisms activated following ligand interactions with the receptors remain poorly defined. Here, we show a membrane controlling mechanism that is initiated by ligand binding to TLR-2, -3 and-4 to induce Neu1 sialidase activity within minutes in live primary bone marrow (BM) macrophage cells and macrophage and dendritic cell lines. Central to this process is that Neu1 and not Neu2,-3 and-4 forms a complex with TLR-2,-3 and-4 on the cell surface of naïve macrophage cells. Neuraminidase inhibitors BCX1827, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir and oseltamivir carboxylate have a limited significant inhibition of the LPS-induced sialidase activity in live BMC-2 macrophage cells but Tamiflu (oseltamivir phosphate) completely blocks this activity. Tamiflu inhibits LPS-induced sialidase activity in live BMC-2 cells with an IC(50) of 1.2 microM compared to an IC(50) of 1015 microM for its hydrolytic metabolite oseltamivir carboxylate. Tamiflu blockage of LPS-induced Neu1 sialidase activity is not affected in BMC-2 cells pretreated with anticarboxylesterase agent clopidogrel. Endotoxin LPS binding to TLR4 induces Neu1 with subsequent activation of NFkappaB and the production of nitric oxide and pro-inflammatory IL-6 and TNFalpha cytokines in primary and macrophage cell lines. Hypomorphic cathepsin A mice with a secondary Neu1 deficiency respond poorly to LPS-induced pro-inflammatory cytokines compared to the wild-type or hypomorphic cathepsin A with normal Neu1 mice. Our findings establish an unprecedented mechanism for pathogen molecule-induced TLR activation and cell function, which is critically dependent on Neu1 sialidase activity associated with TLR ligand treated live primary macrophage cells and macrophage and dendritic cell lines.

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“…These drugs inhibit sialidase activity and are effective against influenza A and B viruses in studies of prevention or early (i.e., within 48 h of infection in animals or onset of clinical symptoms in humans) treatment [17][18][19][20]. Prophylaxis and early treatment reduce the duration and severity of acute influenza, the amount of virus shed, and the levels of proinflammatory cytokines in the upper respiratory tract [18,21].…”

mentioning

confidence: 98%

Role of Neuraminidase in Lethal Synergism between Influenza Virus andStreptococcus pneumoniae

2003

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A lethal synergism exists between influenza virus and Streptococcus pneumoniae, accounting for excess mortality during influenza epidemics. Using a model of viral-bacterial synergism, we assessed the role that the influenza virus neuraminidase (NA) has in priming mice for pneumococcal infection. Administration of the selective NA inhibitor oseltamivir improved survival, independent of viral replication and morbidity from influenza. Both pathologic examination of the lungs and live imaging of pneumonic lesions, using a bioluminescent pneumococcus, suggested that the effect of NA inhibition was to limit the extent of pneumococcal pneumonia during early infection. Adherence assays and immunohistochemical staining for sialic acids in lungs from infected mice demonstrated that the influenza virus NA potentiates development of pneumonia by stripping sialic acid from the lung, thus exposing receptors for pneumococcal adherence. Selective NA inhibitors may be useful clinically to interrupt this novel mechanism of synergism and to prevent excess mortality from secondary bacterial pneumonia.

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Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection

Cited by 242 publications

References 40 publications

Utilization of the embryonated egg for in vivo evaluation of the anti-influenza virus activity of neuraminidase inhibitors

Utilization of the embryonated egg for in vivo evaluation of the anti-influenza virus activity of neuraminidase inhibitors

Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase

Role of Neuraminidase in Lethal Synergism between Influenza Virus andStreptococcus pneumoniae

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