title: Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin.
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 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 nonhuman 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 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.
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors: Evelien
authors: E
authors: Vanderlinden
authors: Els
authors: E
authors: Vanstreels
authors: Eline
authors: E
authors: Boons
authors: Wouter
authors: W
authors: ter Veer
authors: Anke
authors: A
authors: Huckriede
authors: Dirk
authors: D
authors: Daelemans
authors: Alfons
authors: A
authors: Van Lommel
authors: Erzsébet
authors: E
authors: Rőth
authors: Ferenc
authors: F
authors: Sztaricskai
authors: Pàl
authors: P
authors: Herczegh
authors: Lieve
authors: L
authors: Naesens
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000821:virology*; D004285:Dogs; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000502:physiology; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D009981:Influenza B virus / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D015394:Molecular Structure; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006020:Glycopeptides