Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin

Evelien Vanderlinden, Els Vanstreels, Eline Boons, Wouter ter Veer, Anke Huckriede, Dirk Daelemans, Alfons Van Lommel, Erzsébet Röth, Ferenc Sztaricskai, Pàl Herczegh, Lieve Naesens

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Abstract

We report on a new anti-influenza virus agent, SA-19, a lipophilic glycopeptide derivative consisting of aglycoristocetin coupled to a phenylbenzyl-substituted cyclobutenedione. In Madin-Darby canine kidney cells infected with influenza A/H1N1, A/H3N2, or B virus, SA-19 displayed a 50% antivirally effective concentration of 0.60 μMand a selectivity index (ratio of cytotoxic versus antiviral concentration) of 112. SA-19 was 11-fold more potent than unsubstituted aglycoristocetin and was active in human and nonhuman cell lines. Virus yield at 72 h p.i. was reduced by 3.6 logs at 0.8 μMSA-19. In contrast to amantadine and oseltamivir, SA-19 did not select for resistance upon prolonged virus exposure. SA-19 was shown to inhibit an early postbinding step in virus replication. The compound had no effect on hemagglutinin (HA)-mediated membrane fusion in an HA-polykaryon assay and did not inhibit the low-pH-induced refolding of the HA in a tryptic digestion assay. However, a marked inhibitory effect on the transduction exerted by retroviral pseudoparticles carrying an HA or vesicular stomatitis virus glycoprotein (VSV-G) fusion protein was noted, suggesting that SA-19 targets a cellular factor with a role in influenza virus and VSV entry. Using confocal microscopy with antinucleoprotein staining, SA-19 was proven to completely prevent the influenza virus nuclear entry. This virus arrest was characterized by the formation of cytoplasmic aggregates. SA-19 appeared to disturb the endocytic uptake and trap the influenza virus in vesicles distinct from early, late, or recycling endosomes. The aglycoristocetin derivative SA-19 represents a new class of potent and broad-acting influenza virus inhibitors with potential clinical relevance.

Original languageEnglish
Pages (from-to)9416-9431
Number of pages16
JournalJournal of Virology
Volume86
Issue number17
DOIs
Publication statusPublished - Sep 1 2012

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Vanderlinden, E., Vanstreels, E., Boons, E., ter Veer, W., Huckriede, A., Daelemans, D., Van Lommel, A., Röth, E., Sztaricskai, F., Herczegh, P., & Naesens, L. (2012). Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin. Journal of Virology, 86(17), 9416-9431. https://doi.org/10.1128/JVI.07032-11