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, Erzsebet Roth, Ferenc Sztaricskai, Pal Herczegh, Lieve Naesens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 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 mu M and 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 p,M SA-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 con focal 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

Keywords

  • HEPATITIS-C VIRUS
  • GLYCOPEPTIDE ANTIBIOTICS
  • SEMISYNTHETIC DERIVATIVES
  • IN-VITRO
  • NEURAMINIDASE INHIBITORS
  • MULTIVESICULAR BODIES
  • PLATELET-AGGREGATION
  • RESISTANT INFLUENZA
  • RISTOCETIN AGLYCON
  • ANTIVIRAL ACTIVITY

Cite this