Investigating the Relationship Between Helicity and Activity in Antimicrobial Peptides with Stabilized α-Helical Structures

Abstract

Antimicrobial peptides (AMPs) are a novel class of antibiotics comprised of short peptide sequences made up of 5 to 50 amino acids. Of particular interest are α-helical AMPs that kill bacteria through either membrane lysis or translocation and binding to internal targets. Due to their mechanism of action, the ability of α-helical AMPs to interact with biological membranes selectively is critical to generating AMPs with a wide therapeutic window. Of the many biophysical factors to consider when studying this membrane selectivity, secondary structure has been shown to play a critical role. To elucidate the role of helicity in determining AMP membrane selectivity and potency, we have created a library of AMPs with varying stabilized α-helical structures and determined the degree of peptide folding in the presence of liposomes modeled after bacterial and mammalian membranes using circular dichroism (CD) spectroscopy. By correlating our measurements with data from antimicrobial and hemolytic assays, we found that a threshold point existed above which increasing α-helicity diminishes potency and membrane selectivity. The results from this study will aid us in building a biophysical model that could be used for the computational design of new AMPs that have a better chance of being translated into viable clinical treatments.