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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.

ABSTRACT: 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.

SUBMITTER: Tran-To Su C

PROVIDER: S-EPMC3853198 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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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.

Tran-To Su Chinh C Ouyang Xuchang X Zheng Jie J Kwoh Chee-Keong CK

BMC bioinformatics 20131022

<h4>Background</h4>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 perami ...[more]

PMID: 24564719

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Project description:BackgroundResistance of pandemic A(H1N1)2009 (H1N1pdm09) virus to neuraminidase inhibitors (NAIs) has remained limited. A new mutation I223R in the neuraminidase (NA) of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility.MethodsThe NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0-15) and zanamivir (days 15-25 and 70-80).ResultsCompared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246-fold) and oseltamivir and zanamivir (8.9- and 4.9-fold), respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold). In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6-69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin.ConclusionsReduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment underlines the importance of close monitoring of treated patients especially those immunocompromised.

Project description:Influenza virus neuraminidase (NA) drug resistance is one of the challenges to preparedness against epidemic and pandemic influenza virus infections. NA N1- and N2-containing influenza viruses are the primary cause of seasonal epidemics and past pandemics. The structural and functional basis underlying drug resistance of the influenza virus N1 NA is well characterized. Yet drug resistance of the N2 strain is not well understood. Here, we confirm that replacement of N2 E119 or I222 results in multidrug resistance, and when the replacements occur together, the sensitivity to NA inhibitors (NAI) is reduced severely. Using crystallographic studies, we showed that E119 replacement results in a loss of hydrogen bonding to oseltamivir and zanamivir, whereas I222 replacement results in a change in the hydrophobic environment that is critical for oseltamivir binding. Moreover, we found that MS-257, a zanamivir-oseltamivir hybrid inhibitor, is less susceptible to drug resistance. The binding mode of MS-257 shows that increased hydrogen bonding interactions between the inhibitor and NA active site anchor the inhibitor within the active site and allow adjustments in response to active-site modifications. Such stability is likely responsible for the observed reduced susceptibility to drug resistance. MS-257 serves as a next-generation anti-influenza virus drug candidate and serves also as a scaffold for further design of NAIs.ImportanceOseltamivir and zanamivir are the two major antiviral drugs available for the treatment of influenza virus infections. However, multidrug-resistant viruses have emerged in clinical cases, which pose a challenge for the development of new drugs. N1 and N2 subtypes exist in the viruses which cause seasonal epidemics and past pandemics. Although N1 drug resistance is well characterized, the molecular mechanisms underlying N2 drug resistance are unknown. A previous report showed that an N2 E119V/I222L dual mutant conferred drug resistance to seasonal influenza virus. Here, we confirm that these substitutions result in multidrug resistance and dramatically reduced sensitivity to NAI. We further elucidate the molecular mechanism underlying N2 drug resistance by solving crystal structures of the N2 E119V and I222L mutants and the dual mutant. Most importantly, we found that a novel oseltamivir-zanamivir hybrid inhibitor, MS-257, remains more effective against drug-resistant N2 and is a promising candidate as a next-generation anti-influenza virus drug.

Dataset Information

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.

Publications

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.

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