On the Structural Basis of Group 1 Influenza Fusion Inhibition by Arbidol
81 Pages Posted: 21 Feb 2020 Publication Status: Review Complete
More...Abstract
Influenza virus infection continues to be a major healthcare issue and the combination of the strain-specificity of vaccines with the increased circulation of therapeutic resistant strains drives the need for new approaches for the prevention and treatment of infection. Arbidol is a broad-spectrum antiviral with demonstrated activity against both group 1 and 2 influenza hemagglutinin (HA) subtypes. While the Arbidol binding site has been determined for group 2 HAs, it remains unidentified for group 1 HAs. Further, based on differences between group 1 and group 2 HAs, it is unknown whether or not Arbidol binds in a group-specific manner. Here, integrative modeling techniques combining cryo-electron tomography with x-ray crystallography and homology modeling enabled the construction of an all-atom model of the 2009 H1N1 influenza viral coat. Using the petascale supercomputer Blue Waters, we have performed explicitly solvated, all-atom molecular dynamics simulations of this model, which contains over 160 million atoms and spans ~120 nm in diameter. From the subcellular scale simulations, individual HA trajectories have been extracted and analyzed with the construction of a Markov state model. Doing so allows us to investigate the structural dynamics and conformational transitions of the HA glycoprotein in the context of the crowded viral surface. From our Markov state model, we present the first evidence of a druggable pocket in a group 1 HA that is able to accommodate Arbidol. This druggable site is located in an analogous position to the known group 2 Arbidol binding site, suggesting that the binding of Arbidol to influenza HA is not group specific. The structural insights obtained here provide a structural basis for the mechanism of action for this drug in a group 1 HA, and thus will facilitate the development of the next generation of influenza therapeutics.
Keywords: influenza, arbidol, hemagglutinin, molecular dynamics simulation, Markov state model
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