Rupture of Lipid Vesicles by a Broad-Spectrum Antiviral Peptide: Influence of Vesicle Size

Abstract

An amphipathic α-helical (AH) peptide was recently discovered that can rupture the lipid envelope of many viruses including HIV, hepatitis C, dengue, and herpes simplex. Despite its broad-spectrum activity, the AH peptide specifically targets small viruses only and does not affect large viruses. Indirect observations of virus size-specific targeting have been confirmed in a model system comprised of intact lipid vesicles on a gold substrate. Depending on vesicle size, AH peptide can promote vesicle rupture, but the mechanism by which vesicle size influences the rupture process remains to be elucidated. Herein, using the dynamic light scattering and quartz crystal microbalance with dissipation techniques, we have combined experiment and theory to understand the effects of vesicle size on the interaction between the AH peptide and vesicles. We identified that the AH peptide-binding interaction can induce a structural rearrangement of the vesicle's lipid bilayer, which occurs independently of vesicle size. Kinetic analysis also revealed that AH peptide-binding occurs cooperatively for small vesicles only. Binding cooperativity is consistent with pore formation leading to vesicle rupture. By contrast, for large vesicles, AH peptide-binding is noncooperative and does not cause vesicle rupture, suggesting that the binding interaction occurs via a different mechanism. Compared to previous estimates that AH peptide is most effective against viruses with a diameter of less than 70 nm, our evidence validates that AH peptide may target a wider size range of enveloped viruses up to 160 nm in diameter. Taken together, our findings provide a quantitative rationale to understand the targeting specificity of AH peptide as a broad-spectrum antiviral drug candidate.

Correlation between Membrane Partitioning and Functional Activity in a Single Lipid Vesicle Assay Establishes Design Guidelines for Antiviral Peptides

“…For larger vesicles, partitioning was minimal, and indicated that the peptide most likely aggregates on the surface of large vesicles via self‐association . This finding is consistent with a previous report which indicates that AH peptide binds to, but does not rupture, large surface‐immobilized vesicles. Hence, there is a clear distinction between membrane partitioning of AH peptide in small and large vesicles.…”

Plasmonic Nanohole Sensor for Capturing Single Virus‐Like Particles toward Virucidal Drug Evaluation

“…Our study is inspired by the virucidal activity of an amphipathic, α‐helical (AH) peptide which is known to rupture lipid vesicles and exhibits virucidal activity against many kinds of enveloped viruses ( Scheme ). Due to the increasing resistance of many medically important viruses to conventional antiviral drugs, the AH peptide is an attractive drug candidate with a novel mechanism of action based on lipid membrane solubilization .…”

Materials Nanoarchitectonics for Mechanical Tools in Chemical and Biological Sensing

“…[60] However,t his AH peptideo nly ruptures adsorbed vesicles below ac ertain diameter,a nd QCM-Dm easurements identified that the efficiency of vesicle rupture was inversely relatedt o vesicle size. [61] Kinetic analysiso ft he QCM-D measurement data indicated that cooperative peptide binding leads to pore formation and vesicle rupture, whereas noncooperative binding does not cause vesicle rupture. Combined measurement approaches involving QCM-D and ellipsometrye xperiments have further identified that ac riticald ensity of peptide-induced pores form in al ipid vesicle before ruptureo ccurs.…”