Structural basis for oseltamivir resistance of influenza viruses

Collins, Patrick J.; Haire, L.F.; Lin, Yipu; Liu, J.; Russell, Rosemary; Walker, P.A.; Martin, S.R.; Daniels, Rod S.; Gregory, Victoria; Skehel, J.J.; Gamblin, Steve; Hay, Alan J.

doi:10.1016/j.vaccine.2009.07.017

Cited by 104 publications

(106 citation statements)

References 23 publications

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“…The innate immune response plays a key role defense against IAV in the first few days after infection (26). Treatment options include amantadines and neuraminidase inhibitors, although resistance has been observed with increasing frequency (4). An additional problem is that some of the serious illness caused by IAV may relate to inflammatory injury.…”

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confidence: 99%

Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

Nikolaidis

White

Allen

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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confidence: 99%

Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

Nikolaidis

White

Allen

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…H275Y: Antiviral resistance to the neuraminidase inhibitor oseltamivir can be conferred by the well-characterised resistance mutation in the neuraminidase gene H275Y [38,39]. All current seasonal H1N1 (not H1N1 pdm) strains are genotypically (H275Y) and phenotypically resistant to oseltamivir [40,41].…”

Section: Antiviral Resistancementioning

confidence: 99%

“…The emergence of antiviral resistance to chemotherapy is always a cause for concern particularly when compensatory mutations can negate the biological fitness penalty for resistance [38,39,43]. The fact that viruses containing S247N and H275Y have been demonstrated to be transmissible in an animal model [44] indicates that there is scope for resistant mutations to proliferate in the field.…”

Section: Environmental Factors Affecting Genotypementioning

confidence: 99%

“…Ramadhany et al [64] also showed that the minor genotype of α2,3 tropic viruses in upper airways became dominant after passaging through chicken eggs. The affinity for α2,3 has been exploited by making mutations including D222G to produce a H1N1 live attenuated vaccine with enhanced replication in eggs [65].The emergence of antiviral resistance to chemotherapy is always a cause for concern particularly when compensatory mutations can negate the biological fitness penalty for resistance [38,39,43]. The fact that viruses containing S247N and H275Y have been demonstrated to be transmissible in an animal model [44] indicates that there is scope for resistant mutations to proliferate in the field.…”

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confidence: 99%

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Risk Factors Associated with Severe Clinical Outcomes of Pandemic H1N1 Infection

Fullen¹

2014

JHVRV

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The clinical outcome of pandemic H1N1 influenza infection is dependent on the interplay of virus and host factors. Influenza virus infections can range from relatively mild infections of the upper respiratory tract to fatal disease of the lower respiratory tract. A range of host factors play a role in the severity of clinical disease in pdm(H1N1)09 infection. With the exception of neonates age was directly proportional to the severity of clinical outcome; obesity, COPD and pregnancy play a key role in clinical outcome of infection. An important determinant in the pathogenesis of influenza infection is the tissue tropism of the influenza virus. The D222G and D222N mutations of pdm(H1N1)09 influenza appear to have an increased tropism for the tissues of the lower respiratory tract and are disproportionally associated with severe clinical disease. These α2-3 salicylic acid tropic mutations, which have been associated with fatal cases of influenza infection, have also been preferentially selected for during sequential passage in embryonated eggs and viruses of avian origin. KeywordsInfluenza; Pandemic; H1N1; pdm(H1N1)09; Oseltamivir IntroductionThe current H1N1 influenza vaccine strain A/ California/7/2009 has a surprisingly high no detectable antibody (NDA) rate of approximately 52% in a population of 200 subjects screened (unpublished data). Studies have shown that the A/California/7/2009 strain of pandemic H1N1 influenza causes alveolar haemorrhage in the ferret model [1,2]; similar "swine flu" viruses A/Mexico/4482/2009 and A/ Netherlands/602/2009 also presented severe pathology in the ferret model [3,4]. As a consequence it is clear that infection with this group of viruses represents a significant risk of a severe clinical outcome. Furthermore, the severe symptoms that are associated with a subset of A/California/7/2009 infections are atypical for previous seasonal influenza infections. Co-morbidities and their impact on clinical outcome of infectionThe clinical outcomes of infection by pdm(H1N1)09 are considerably affected by one or more host factors and comorbidities. Here we discuss these co-morbidities and the impact that they have on clinical consequences to infection. Case fatality ratiosBy July 2009 63,479 cases of influenza like illness were reported in Mexico; of these cases 11% (6,945) were confirmed as H1N1 influenza; 92% of confirmed positive cases (6,407) were treated as outpatients, 7% (475) were admitted to hospital and survived and <1% died (63) [5]. During the early phase of the pandemic the case fatality ratio (CFR) was calculated to be approximately 0.4-0.6% [6]. In the UK an estimated 540,000 people had symptomatic H1N1 infection during a study period with a CFR of (0.026%) 26 deaths per 100,000 [7]. There is little published information for the CFRs of seasonal H1N1 or H3N2 influenza. However using data from the Health Protection Agency (HPA) we were able to determine the CFR for influenza infections admitted to intensive care units (ICU). 2/7 SymptomsA meta-analysis of H1N1...

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“…By far the most common of these mutations, H274Y, restricts the inhibition of oseltamivir by displacing the pentyloxy group out of a hydrophobic pocket close to the active site [16][17][18][19] Other mutations, particularly E119V, E119G, and R292K can affect binding of both oseltamivir and zanamivir but arise much less frequently 20,21 Drug resistance and environmental influences helped this adaptive mutation of the strains to promote its efficacy multiple times than normal 22 . Thus, neuraminidase is a promising drug target for the treatment of various influenza viruses.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2016

IJPSR

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ABSTRACT:Inhibition of viral coating protein is an established therapeutic strategy for the treatment of many influenza treatment regimes. Although resistance to such inhibitors is common phenomena in different influenza treatment, such resistance can be averted by targeting coating proteins with phytochemicals. Swine Flu neuraminidase protein (H1N1) has been currently focused target for influenza inhibitor research. We used computational high throughput screening approach to identify novel phytochemical inhibitors from phytochemical knowledgebase. Our computational method used in this study is an integration of qualitative models obtained from consensus hydrated virtual screening protocols for H1N1 Neuraminidase 1 (N1) to identify the novel phytochemical inhibitors. Using the available N1 crystal structures in protein databank flexibility and hydration states were analyzed and validated. The three representative crystal structures with open and closed conformations with highly conserved waters were used to screened the phytochemical database and identified novel inhibitors, among them a first in class alkaloids inhibitor that have shown better affinity against neuraminidase protein over marketed drugs. Our studies suggest that this computational screening approach may be broadly applicable for identifying inhibitors with potential for treating H1N1.

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Structural basis for oseltamivir resistance of influenza viruses

Cited by 104 publications

References 23 publications

Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

Risk Factors Associated with Severe Clinical Outcomes of Pandemic H1N1 Infection

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