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Published ahead of print 27 June 2012, doi: 10.1128/JVI.07032-11
Evelien Vanderlindena,
Els Vanstreelsa,
Eline Boonsa,
Wouter ter Veerc,
Anke Huckriedec,
Dirk Daelemansa,
Alfons Van Lommeld,
Erzs?bet Rőthb,
Ferenc Sztaricskaib,
P?l Herczeghb,* and
Lieve Naesensa,*
+ Author Affiliations
aRega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium
bDepartment of Pharmaceutical Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
cDepartment of Medical Microbiology, Molecular Virology Section, University Medical Center and University of Groningen, Groningen, The Netherlands
dDepartment of Medical Diagnostic Sciences, KU Leuven, B-3000 Leuven, Belgium
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 viruses, SA-19 displayed a 50% antivirally effective concentration of 0.60 μM 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 non-human cell lines. Virus yield at 72 h p.i. was reduced by 3.6 logs at 0.8 μM 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 post-binding 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 was noted on the transduction by retroviral pseudoparticles carrying an HA or VSV-G fusion protein, suggesting that SA-19 targets a cellular factor with a role in influenza virus and VSV entry. Using confocal microscopy with anti-nucleoprotein 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.
http://jvi.asm.org/content/early/2012/06/20/JVI.07032-11.abstract
Evelien Vanderlindena,
Els Vanstreelsa,
Eline Boonsa,
Wouter ter Veerc,
Anke Huckriedec,
Dirk Daelemansa,
Alfons Van Lommeld,
Erzs?bet Rőthb,
Ferenc Sztaricskaib,
P?l Herczeghb,* and
Lieve Naesensa,*
+ Author Affiliations
aRega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium
bDepartment of Pharmaceutical Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
cDepartment of Medical Microbiology, Molecular Virology Section, University Medical Center and University of Groningen, Groningen, The Netherlands
dDepartment of Medical Diagnostic Sciences, KU Leuven, B-3000 Leuven, Belgium
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 viruses, SA-19 displayed a 50% antivirally effective concentration of 0.60 μM 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 non-human cell lines. Virus yield at 72 h p.i. was reduced by 3.6 logs at 0.8 μM 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 post-binding 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 was noted on the transduction by retroviral pseudoparticles carrying an HA or VSV-G fusion protein, suggesting that SA-19 targets a cellular factor with a role in influenza virus and VSV entry. Using confocal microscopy with anti-nucleoprotein 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.
http://jvi.asm.org/content/early/2012/06/20/JVI.07032-11.abstract