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Viruses 2018, 10(6), 306; https://doi.org/10.3390/v10060306

1-Benzyl-3-cetyl-2-methylimidazolium Iodide (NH125) Is a Broad-Spectrum Inhibitor of Virus Entry with Lysosomotropic Features

1
Institut für Virologie und Immunologie (IVI), Abteilung Virologie, CH-3147 Mittelhäusern, Switzerland
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
*
Author to whom correspondence should be addressed.
Received: 17 April 2018 / Accepted: 28 May 2018 / Published: 5 June 2018
(This article belongs to the Section Antivirals & Vaccines)
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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. View Full-Text
Keywords: eukaryotic elongation factor 2 kinase; kinase inhibitor; membrane fusion; alkylated imidazolium; ionic liquid; virus entry; enveloped virus; lysosomotropic agent eukaryotic elongation factor 2 kinase; kinase inhibitor; membrane fusion; alkylated imidazolium; ionic liquid; virus entry; enveloped virus; lysosomotropic agent
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Moeschler, S.; Locher, S.; Zimmer, G. 1-Benzyl-3-cetyl-2-methylimidazolium Iodide (NH125) Is a Broad-Spectrum Inhibitor of Virus Entry with Lysosomotropic Features. Viruses 2018, 10, 306.

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