Mechanistic analysis of antiviral peptide interactions with supported lipid bilayers using polarised neutron reflectometry

Broad-spectrum antiviral peptides that inhibit membrane-enveloped viruses represent a next-generation antiviral strategy for future pandemic preparedness. The AH and C5A peptides are two important antiviral peptides, however, the atomistic details of how these two peptides distinctly interact with lipid membranes remain unknown. Addressing this gap is critical from a translational perspective because the AH peptide selectively targets highly curved membranes such as those of virus particles and leaves human cell membranes unperturbed whereas the C5A peptide indiscriminately solubilizes high- and low-curvature membranes. In this project, we will study the membrane-disruptive interactions of AH and C5A peptides with supported lipid bilayers (SLBs) by using polarised neutron reflectometry (PNR). We plan to use solid substrates that have an iron magnetic-reference layer and an outer silicon oxide surface. Use of the magnetic reference layer will allow us to enhance the resolution to details of the peptide-lipid interaction and will expand on our preliminary NR data showing the effects of AH and C5A peptide addition to a POPC SLB, including dissecting the interplay of peptide penetration into the SLB and peptide-mediated lipid removal. The resulting insights will aid understanding of the potential clinical utility of these peptides while providing mechanistic guidance to engineer improved antiviral peptides, especially in combination with other biophysical and modeling efforts.