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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

28 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)9416-9431
Aantal pagina's16
TijdschriftJournal of Virology
Volume86
Nummer van het tijdschrift17
DOI's
StatusPublished - sep-2012

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