title: Single vesicle analysis reveals nanoscale membrane curvature selective pore formation in lipid membranes by an antiviral α-helical peptide.
abstract: Using tethered sub-100 nm lipid vesicles that mimic enveloped viruses with nanoscale membrane curvature, we have in this work designed a total internal reflection fluorescence microscopy-based single vesicle assay to investigate how an antiviral amphipathic α-helical (AH) peptide interacts with lipid membranes to induce membrane curvature-dependent pore formation and membrane destabilization. Based on a combination of statistics from single vesicle imaging, binding kinetics data, and theoretical analysis, we propose a mechanistic model that is consistent with the experimentally observed peptide association and pore formation kinetics at medically relevant peptide concentrations (10 nM to 1 μM) and unusually low peptide-to-lipid (P/L) ratio (~1/1000). Importantly, the preference of the AH peptide to selectively rupture virions with sub-100 nm diameters appears to be related to membrane strain-dependent pore formation rather than to previously observed nanoscale membrane curvature facilitated binding of AH peptides. Compared to other known proteins and peptides, the combination of low effective P/L ratio and high specificity for nm-sized membrane curvature lends this particular AH peptide great potential to serve as a framework for developing a highly specific and potent antiviral agent for prophylactic and therapeutic applications while avoiding toxic side effects against host cell membranes.
authors.affiliation: Department of Applied Physics, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Seyed R
authors.initials: SR
authors.lastname: Tabaei
authors.forename: Michael
authors.initials: M
authors.lastname: Rabe
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Zhdanov
authors.forename: Nam-Joon
authors.initials: NJ
authors.lastname: Cho
authors.forename: Fredrik
authors.initials: F
authors.lastname: Höök
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001710:Biotin / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D005452:Fluoresceins / Q000737:chemistry; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008563:Membrane Lipids / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods*; D010455:Peptides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D017433:Protein Structure, Secondary; D012235:Rhodamines / Q000737:chemistry; D012680:Sensitivity and Specificity; D020349:Surface Plasmon Resonance; D013499:Surface Properties
chemical_list: D000998:Antiviral Agents; D005452:Fluoresceins; D008055:Lipids; D008563:Membrane Lipids; D010455:Peptides; D010713:Phosphatidylcholines; D012235:Rhodamines; D001710:Biotin; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; C007740:fluorexon