title: Potential of acylated peptides to target the influenza A virus.
abstract: For antiviral drug design, especially in the field of influenza virus research, potent multivalent inhibitors raise high expectations for combating epidemics and pandemics. Among a large variety of covalent and non-covalent scaffold systems for a multivalent display of inhibitors, we created a simple supramolecular platform to enhance the antiviral effect of our recently developed antiviral Peptide B (PeB(GF)), preventing binding of influenza virus to the host cell. By conjugating the peptide with stearic acid to create a higher-order structure with a multivalent display, we could significantly enhance the inhibitory effect against the serotypes of both human pathogenic influenza virus A/Aichi/2/1968 H3N2, and avian pathogenic A/FPV/Rostock/34 H7N1 in the hemagglutination inhibition assay. Further, the inhibitory potential of stearylated PeB(GF) (C18-PeB(GF)) was investigated by infection inhibition assays, in which we achieved low micromolar inhibition constants against both viral strains. In addition, we compared C18-PeB(GF) to other published amphiphilic peptide inhibitors, such as the stearylated sugar receptor mimicking peptide (Matsubara et al. 2010), and the "Entry Blocker" (EB) (Jones et al. 2006), with respect to their antiviral activity against infection by Influenza A Virus (IAV) H3N2. However, while this strategy seems at a first glance promising, the native situation is quite different from our experimental model settings. First, we found a strong potential of those peptides to form large amyloid-like supramolecular assemblies. Second, in vivo, the large excess of cell surface membranes provides an unspecific target for the stearylated peptides. We show that acylated peptides insert into the lipid phase of such membranes. Eventually, our study reveals serious limitations of this type of self-assembling IAV inhibitors.
authors.affiliation: Humboldt-Universität zu Berlin, Institute of Biology, Invalidenstr. 42, 10115 Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lauster
authors.affiliation: Humboldt-Universität zu Berlin, Institute of Biology, Invalidenstr. 42, 10115 Berlin, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Pawolski
authors.affiliation: Humboldt-Universität zu Berlin, Institute of Biology, Invalidenstr. 42, 10115 Berlin, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Storm
authors.affiliation: Freie Universität Berlin, Research Center of Electron Microscopy, Fabeckstr. 36a, 14195 Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Ludwig
authors.affiliation: Charité Universitätsmedizin Berlin, Institute of Immunology, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Am Mühlenberg 13, 14476 Potsdam, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Memczak
authors.affiliation: Humboldt-Universität zu Berlin, Institute of Biology, Invalidenstr. 42, 10115 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.affiliation: Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustr. 3, 14195 Berlin, Germany.
authors.forename: Sumati
authors.initials: S
authors.lastname: Bhatia
keywords: amphiphilic peptide; antiviral; influenza virus; multivalency; self-assembled structures