Mechanism of Drug Resistance of Hemagglutinin of Influenza Virus and Potent Scaffolds Inhibiting Its Function

Abstract

Highly pathogenic influenza viruses have become a global threat to humans. It is important to select an effective therapeutic option suitable for the subtypes in an epidemic or pandemic. To increase the options, the development of novel antiviral agents acting on targets different from those of the currently approved drugs is required. In this study, we performed molecular dynamics simulations on a spike protein on the viral envelop, hemagglutinin, for the wild-type and three kinds of mutants using a model system consisting of a trimeric hemagglutinin complex, viral lipid membrane, solvation waters, and ions. A natural product, stachyflin, which shows a high level of antiviral activity specific to some subtypes of influenza viruses, was examined on binding to the wild-type hemagglutinin by docking simulation. The compound potency of stachyflin is, however, easily lost due to resistant mutations. From a comparison of simulation results between the wild-type and the resistant mutants, the reason for the drug resistance of hemagglutinin was clarified. Next, 8 compounds were selected from a chemical database by in silico screening, considering the findings from the simulations. Inhibitory activities to suppress the proliferation of influenza virus were measured by cell-based antiviral assays, and two chemical scaffolds were found to be potent for an inhibitor. More than 30 derivatives bearing either of these two chemical scaffolds were synthesized, and cell culture assays were carried out to evaluate the compound potency. Several derivatives displayed a high compound potency, and 50% effective concentrations of two synthesized compounds were below 1 μM.

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“…25,29,30) In short, the production run was carried out at a temperature of 310 K and a pressure of 1 atm. A periodic boundary condition was applied to all of the xyz-directions, and pressure and temperature were kept constant.…”

“…The Cterminal domain of Aβ 42 , residue [29][30][31][32][33][34][35][36][37][38][39][40][41][42], is composed of nonpolar residues and thus has strong hydrophobicity. The domain contains 4 Glys, which enhance the structural flexibility and increase the tendency for formation of a coil or a bend in the secondary structure.…”

Effect of altering local protein fluctuations using artificial intelligence

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Antiviral agents targeting the influenza virus: a review and publication analysis

“…In response to the emergence of some oseltamivir-resistant influenza strains, peramivir and laninamivir have been recently developed (Bantia et al 2006;Kubo et al 2010). New-generation neuraminidase inhibitors are currently under investigation, e.g., multimeric forms of zanamivir (Watson et al 2004), dual-targeted bifunctional antivirals (Liu et al 2012), and several herbal remedies, such as flavonols, alkaloids and saponins (Jeong et al 2009). The key publications on the structure, synthesis and therapeutic application of neuraminidase inhibitors are presented in Table 4.4.…”