Abstract
BackgroundSince 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.ResultsCombination 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.ConclusionsThe 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.
Highlights
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
Mutation R289K causes different conformational changes in the structure of the H7N9 Neuraminidase when it interacts with oseltamivir, zanamivir, and peramivir We used 3 current approved neuraminidase inhibitors, which are applied in the treatment of the influenza A (H7N9), to dock independently as ligand to the non-mutated structure of the H7N9 neuraminidase (NA) using Autodock 4.2 [21]
Our results indicate that the mutation R289K may result in reducing the drug susceptibility of the viral strain
Summary
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. 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 There has been another global health concern since the last few months by the emergence of a novel strain of avian influenza A (H7N9) virus, which has never been detected in humans [1,2]. According to World Health Organization (WHO), this avian influenza A (H7N9) strain is considered to be one of the most lethal influenza viruses [4] because reported infections occur sporadically, and asymptomatically (i.e. one patient case found in Beijing, China) [2] This novel low-pathogenic H7N9 strain does not cause disease symptoms in animals; it escapes detection from animal reservoir and has higher probability to transmit than the previous highly pathogenic H5N1 strain, which killed hundreds worldwide [5,6]. It could be just a matter of time before the new strain of virus can pose a potential human pandemic
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