Abstract
Cellular kinases are crucial for the transcription/replication of many negative-strand RNA viruses and might serve as targets for antiviral therapy. In this study, a library comprising 80 kinase inhibitors was screened for antiviral activity against vesicular stomatitis virus (VSV), a prototype member of the family Rhabdoviridae. 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125), an inhibitor of eukaryotic elongation factor 2 (eEF2) kinase, significantly inhibited entry of single-cycle VSV encoding a luciferase reporter. Treatment of virus particles had only minimal effect on virus entry, indicating that the compound primarily acts on the host cell rather than on the virus. Accordingly, resistant mutant viruses were not detected when the virus was passaged in the presence of the drug. Unexpectedly, NH125 led to enhanced, rather than reduced, phosphorylation of eEF2, however, it did not significantly affect cellular protein synthesis. In contrast, NH125 revealed lysosomotropic features and showed structural similarity with N-dodecylimidazole, a known lysosomotropic agent. Related alkylated imidazolium compounds also exhibited antiviral activity, which was critically dependent on the length of the alkyl group. Apart from VSV, NH125 inhibited infection by VSV pseudotypes containing the envelope glycoproteins of viruses that are known to enter cells in a pH-dependent manner, i.e. avian influenza virus (H5N1), Ebola virus, and Lassa virus. In conclusion, we identified an alkylated imidazolium compound which inhibited entry of several viruses not because of the previously postulated inhibition of eEF2 kinase but most likely because of its lysosomotropic properties.
Highlights
In recent decades an increasing number of chemotherapies have become available for the treatment of viral infections, e.g., drugs with antiviral activity against herpesviruses, HIV-1, influenzaA virus, or hepatitis C virus [1]
Imidazolium derivatives with either a shorter aliphatic side chain (1-hexyl-3-methylimidazolium iodide, Hexyl-MI). Without such a side group (1-benzyl-3-methylimidazolium chloride, Benzyl-MI) (Figure 3b) showed no, or low, antiviral activity. These findings suggested that NH125-related imidazolium derivatives may exhibit antiviral activity, which critically depends on the length of the aliphatic side chain
In accordance with our findings presented in the previous abolished in the presence of 10 μ M or 5 μ M of NH125, while lower concentrations of NH125 reduced section, cell surface expression of vesicular stomatitis virus (VSV) G protein in this cell line was not affected by NH125 (Figure 5a)
Summary
In recent decades an increasing number of chemotherapies have become available for the treatment of viral infections, e.g., drugs with antiviral activity against herpesviruses, HIV-1, influenzaA virus, or hepatitis C virus [1]. In recent decades an increasing number of chemotherapies have become available for the treatment of viral infections, e.g., drugs with antiviral activity against herpesviruses, HIV-1, influenza. The majority of antiviral therapies target a specific viral protein, e.g., a component of the viral replication machinery. Drugs belonging to this category are less likely to cause side effects compared to drugs targeting a cellular component, but they may select more for drug-resistant mutant viruses. This is in particular true for RNA viruses which possess error-prone. Drugs for the treatment of newly emerging viruses are not readily available
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