2 research outputs found
J Infect Dis
Background.Patients contracting influenza A(H7N9) infection often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drugresistance markers for influenza A(H7N9) is limited.Methods.Four NA variants of A/Taiwan/1/2013(H7N9) virus containing a single substitution (NA-E119V, NA-I222K, NA-I222R, or NA-R292K) recovered from an oseltamivir-treated patient were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice, and ferrets.Results.NA-R292K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119V, NA-I222K, and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA-R292K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of NA-I222K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract but produced only mild illness. NA-R292K virus, showed reduced replicative fitness in this animal model.Conclusions.Our data highlight challenges in assessment of the replicative fitness of H7N9 NA variants that emerged in NAI-treated patients.20142020-01-06T00:00:00ZCC999999/ImCDC/Intramural CDC HHS/United States25124927PMC6943751754
Structural analysis of the novel influenza A (H7N9) viral Neuraminidase interactions with current approved neuraminidase inhibitors Oseltamivir, Zanamivir, and Peramivir in the presence of mutation R289K
Background: Since late March 2013, there has been another global health concern with a sudden wave of flu
infections by a novel strain of avian influenza A (H7N9) virus in China. To-date, there have been more than 100
infections with 23 deaths. It is more worrying as this viral strain has never been detected in humans and only been
found to be of low-pathogenicity. Currently, there are 3 effective neuraminidase inhibitors for this H7N9 virus strain,
i.e. oseltamivir, zanamivir, and peramivir. These drugs have been used for treatment of the H7N9 influenza in China.
However, how these inhibitors work and affect the binding cavity of the novel H7N9 neuraminidase in the
presence of potential mutations has not been disclosed. In our study, we investigate steric effects and
subsequently show the conformational restraints of the inhibitor-binding site of the non-mutated and mutated
H7N9 neuraminidase structures to different drug compounds.
Results: Combination of molecular docking and Molecular Dynamics simulation reveal that zanamivir forms more
favorable and stable complex than oseltamivir and peramivir when binding to the active site of the H7N9
neuraminidase. And it is likely that the novel influenza A (H7N9) virus adopts a higher probability to acquire
resistance to peramivir than the other two inhibitors. Conformational changes induced by the mutation R289K
causes loss of number of hydrogen bonds between the inhibitors and the H7N9 viral neuraminidase in 2 out of 3
complexes. In addition, our results of binding-affinity relationships of the 3 inhibitors with the viral neuraminidase
proteins of previous pandemics (H1N1, H5N1) and the current novel H7N9 reflected the extent of binding
effectiveness of the 3 inhibitors to the novel H7N9 neuraminidase.
Conclusions: The results are novel and specific for the A/Hangzhou/1/2013(H7N9) influenza strain. Furthermore,
the protocol could be useful for further drug-binding analysis and prediction of future viral mutations to which the
virus evolves through adaptation and acquires resistance to the current available drugs.MOE (Min. of Education, S’pore)Published versio