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, F. Sztaricskai, P. Herczegh, Lieve Naesens

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 2012

Fingerprint

Orthomyxoviridae
trapping
Hemagglutinins
hemagglutinins
chemical derivatives
Virus Internalization
Viruses
viruses
Viral Fusion Proteins
Macacine herpesvirus 1
H3N2 Subtype Influenza A Virus
Oseltamivir
Vesiculovirus
glycopeptides
Cercopithecine Herpesvirus 1
Amantadine
Vesicular Stomatitis
Madin Darby Canine Kidney Cells
Membrane Fusion
endosomes

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Vanderlinden, E., Vanstreels, E., Boons, E., ter Veer, W., Huckriede, A., Daelemans, D., ... 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

Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin. / Vanderlinden, Evelien; Vanstreels, Els; Boons, Eline; ter Veer, Wouter; Huckriede, Anke; Daelemans, Dirk; Van Lommel, Alfons; Röth, Erzsébet; Sztaricskai, F.; Herczegh, P.; Naesens, Lieve.

In: Journal of Virology, Vol. 86, No. 17, 09.2012, p. 9416-9431.

Research output: Contribution to journalArticle

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, vol. 86, no. 17, pp. 9416-9431. https://doi.org/10.1128/JVI.07032-11
Vanderlinden E, Vanstreels E, Boons E, ter Veer W, Huckriede A, Daelemans D et al. Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin. Journal of Virology. 2012 Sep;86(17):9416-9431. https://doi.org/10.1128/JVI.07032-11
Vanderlinden, Evelien ; Vanstreels, Els ; Boons, Eline ; ter Veer, Wouter ; Huckriede, Anke ; Daelemans, Dirk ; Van Lommel, Alfons ; Röth, Erzsébet ; Sztaricskai, F. ; Herczegh, P. ; Naesens, Lieve. / Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin. In: Journal of Virology. 2012 ; Vol. 86, No. 17. pp. 9416-9431.
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