Abstract
In March 2013, a novel avian influenza A (H7N9) virus emerged in China. By March 2021, it had infected more than 1500 people, raising concerns regarding its epidemic potential. Similar to the highly pathogenic H5N1 virus, the H7N9 virus causes severe pneumonia and acute respiratory distress syndrome in most patients. Moreover, genetic analysis showed that this avian H7N9 virus carries human adaptation markers in the hemagglutinin and polymerase basic 2 (PB2) genes associated with cross-species transmissibility. Clinical studies showed that a single mutation, neuraminidase (NA) R292K (N2 numbering), induces resistance to peramivir in the highly pathogenic H7N9 influenza A viruses. Therefore, to evaluate the risk for human public health and understand the possible source of drug resistance, we assessed the impact of the NA-R292K mutation on avian H7N9 virus resistance towards peramivir using various molecular dynamics approaches. We observed that the single point mutation led to a distorted peramivir orientation in the enzyme active site which, in turn, perturbed the inhibitor’s binding. The R292K mutation induced a decrease in the interaction among neighboring amino acid residues when compared to its wild-type counterpart, as shown by the high degree of fluctuations in the radius of gyration. MM/GBSA calculations revealed that the mutation caused a decrease in the drug binding affinity by 17.28 kcal/mol when compared to the that for the wild-type enzyme. The mutation caused a distortion of hydrogen bond-mediated interactions with peramivir and increased the accessibility of water molecules around the K292 mutated residue.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
The impact of the single point mutation R292K on pathogenic H7N9 in influenza neuraminidase on peramivir binding to the enzyme was investigated using various computational approaches
These approaches, including MD simulations, principal component analysis, root-mean-square deviation, radius of gyration, and solvent-accessible surface area, aided us to understand the impact of the R292K mutation on resistance to peramivir
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The seasonal upsurge of infections and pandemics from influenza viruses continues to cause death and morbidity. This poses great economic stress and decreases productivity, especially in countries with temperate and tropical weather conditions [1,2]. The influenza virus is classified as Orthomyxoviridae, with classes A and B responsible for pandemic upsurges in humans [3,4]. The influenza virus contains three membrane proteins, i.e., matrix protein (M2), hemagglutinin (HA), and neuraminidase (NA) [5].
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