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Concept: Zanamivir

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Without baseline human immunity to the emergent avian influenza A(H7N9) virus, neuraminidase inhibitors are vital for controlling viral replication in severe infections. An amino acid change in the viral neuraminidase associated with drug resistance, NA-R292K (N2 numbering), has been found in some H7N9 clinical isolates. Here we assess the impact of the NA-R292K substitution on antiviral sensitivity and viral replication, pathogenicity and transmissibility of H7N9 viruses. Our data indicate that an H7N9 isolate encoding the NA-R292K substitution is highly resistant to oseltamivir and peramivir and partially resistant to zanamivir. Furthermore, H7N9 reassortants with and without the resistance mutation demonstrate comparable viral replication in primary human respiratory cells, virulence in mice and transmissibility in guinea pigs. Thus, in stark contrast to oseltamivir-resistant seasonal influenza A(H3N2) viruses, H7N9 virus replication and pathogenicity in these models are not substantially altered by the acquisition of high-level oseltamivir resistance due to the NA-R292K mutation.

Concepts: Virus, Antiviral drug, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor

36

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here a new class of specific, mechanism-based anti-influenza drugs that function via the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and confirm this mode of action via structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.

Concepts: Enzyme, Antiviral drug, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor

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The wizard of OS (resistance): The binding difference of neuraminidase inhibitors (zanamivir versus oseltamivir (OS)) was used to establish an assay to identify the influenza subtypes that are resistant to OS but still sensitive to zanamivir. This assay used a zanamivir-biotin conjugate to determine the OS susceptibility of a wide range of influenza viruses and over 200 clinical isolates.

Concepts: Antibiotic resistance, Antiviral drug, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor

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The first structure determination of a neuraminidase inhibitor, oseltamivir phosphate, the active component of the anti-influenza agent Tamiflu, was achieved by single crystal X-ray diffraction with synchrotron radiation. The structure reproduces to a great extent the binding of the inhibitor in the neuraminidase active site and provides more accurate structural parameters as well as detailed insight into the binding preferences of the inhibitor.

Concepts: Electron, X-ray, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor

4

OBJECTIVE:Timely treatment with neuraminidase inhibitor (NAI) drugs appears to improve survival in adults hospitalized with influenza. We analyzed California surveillance data to determine whether NAI treatment improves survival in critically ill children with influenza.METHODS:We analyzed data abstracted from medical records to characterize the outcomes of patients aged 0 to 17 years hospitalized in ICUs with laboratory-confirmed influenza from April 3, 2009, through September 30, 2012.RESULTS:Seven hundred eighty-four influenza cases aged <18 years hospitalized in ICUs had information on treatment. Ninety percent (532 of 591) of cases during the 2009 H1N1 pandemic (April 3, 2009-August 31, 2010) received NAI treatment compared with 63% (121 of 193) of cases in the postpandemic period (September 1, 2010-September 30, 2012; P < .0001). Of 653 cases NAI-treated, 38 (6%) died compared with 11 (8%) of 131 untreated cases (odds ratio = 0.67, 95% confidence interval: 0.34-1.36). In a multivariate model that included receipt of mechanical ventilation and other factors associated with disease severity, the estimated risk of death was reduced in NAI-treated cases (odds ratio 0.36, 95% confidence interval: 0.16-0.83). Treatment within 48 hours of illness onset was significantly associated with survival (P = .04). Cases with NAI treatment initiated earlier in illness were less likely to die.CONCLUSIONS:Prompt treatment with NAIs may improve survival of children critically ill with influenza. Recent decreased frequency of NAI treatment of influenza may be placing untreated critically ill children at an increased risk of death.

Concepts: Influenza, Swine influenza, Pandemic, 2009 flu pandemic, Influenza A virus subtype H1N1, Neuraminidase, Zanamivir, Peramivir

3

The Influenza Resistance Information Study (IRIS) was initiated in 2008 to study the emergence of neuraminidase inhibitor (NAI) resistance and the clinical course of influenza in immunocompetent treated and untreated patients.

Concepts: Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Influenzavirus A, Neuraminidase inhibitor

3

Influenza causes substantial morbidity and mortality worldwide. Few data exist for the efficacy of neuraminidase inhibitors, which are the only readily available influenza treatment options, especially in low-income settings. We assessed the efficacy of treatment with the neuraminidase inhibitor oseltamivir to reduce patient illness and viral shedding in people with influenza, in whom treatment was started within 5 days of symptom onset, in an urban setting in Bangladesh.

Concepts: Virus, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Viral shedding, Neuraminidase inhibitor

2

We report characteristics of oseltamivir-resistant influenza A(H1N1)pdm09 viruses and patients infected with these viruses in the United States. During 2013-14, fifty-nine (1.2%) of 4,968 analyzed US influenza A(H1N1)pdm09 viruses had the H275Y oseltamivir resistance-conferring neuraminidase substitution. Our results emphasize the need for local surveillance for neuraminidase inhibitor susceptibility among circulating influenza viruses.

Concepts: United States, Antiviral drug, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor

1

Despite being a common viral disease, influenza has very negative consequences, causing the death of around half a million people each year. A neuraminidase located on the surface of the virus plays an important role in viral reproduction by contributing to the release of viruses from infected host cells. The treatment of influenza is mainly based on the administration of neuraminidase inhibitors. The neuraminidase inhibitors zanamivir, laninamivir, oseltamivir and peramivir have been commercialized and have been demonstrated to be potent influenza viral neuraminidase inhibitors against most influenza strains. In order to create more potent neuraminidase inhibitors and fight against the surge in resistance resulting from naturally-occurring mutations, these anti-influenza drugs have been used as templates for the development of new neuraminidase inhibitors through structure-activity relationship studies. Here, we review the synthetic routes to these commercial drugs, the modifications which have been performed on these structures and the effects of these modifications on their inhibitory activity.

Concepts: Organism, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors

1

Long-term chemoprophylaxis using neuraminidase inhibitors may be needed during influenza epidemics but safety data are limited to several weeks. We sought to assess the tolerability of oseltamivir and zanamivir as primary prophylaxis over 16 weeks.

Concepts: Health care, Influenza, Oseltamivir, Neuraminidase, Viral neuraminidase, Zanamivir, Neuraminidase inhibitor, Neuraminidase inhibitors