Comparing the Membrane-Interaction Profiles of Two Antiviral Peptides: Insights into Structure-Function Relationship

Area of Science:

• Biophysics
• Structural Biology
• Antiviral Therapeutics

Background:

• Amphipathic, α-helical peptides can inhibit enveloped viruses by disrupting their lipid membranes.
• Understanding the structure-function relationship of these peptides is crucial for developing effective antiviral strategies.
• A small subset of these peptides exhibits significant inhibitory activity, necessitating detailed investigation into their mechanisms.

Purpose of the Study:

• To investigate the interaction of biologically active peptides AH and C5A with model lipid membranes.
• To elucidate how membrane environments induce conformational changes in these peptides.
• To understand the distinct mechanisms by which AH and C5A peptides disrupt lipid membranes.

Main Methods:

• Circular dichroism spectroscopy to monitor peptide conformational changes.
• Time-lapsed fluorescence microscopy to observe peptide-induced lipid vesicle lysis.
• Electrochemical impedance spectroscopy on tethered lipid bilayers to analyze membrane disruption.
• Computational simulations to model peptide-membrane interactions and conformational dynamics.

Main Results:

• Both AH and C5A peptides exhibit coil-to-helix transitions in lipid environments, with C5A showing a larger change.
• C5A potently lyses lipid vesicles at low concentrations, while AH preferentially targets vesicles with high membrane curvature.
• C5A solubilizes lipid membranes, whereas AH disrupts them via pore formation, supported by distinct helical folding patterns.
• AH monomers form two short helices, while C5A monomers form a single helix.

Conclusions:

• Membrane-active antiviral peptides display distinct interaction profiles and targeting selectivities based on their structure.
• The structural insights gained are valuable for engineering more effective peptide-based antiviral agents.
• Different helical folding patterns dictate the specific mechanisms of membrane disruption by AH and C5A peptides.