Role of the Side Chains in the Activity of Cyclic N-Substituted Glycine Oligomers

Abstract

Non-natural mimics of antimicrobial peptides (AMPs) can be designed to display chemical moieties analogous to the active side chains of natural peptides, while its abiotic backbone provides protection from proteolytic degradation. A discrete conformational structure of a molecule is commonly accepted to be another prerequisite for potent antimicrobial activity. N-substituted glycine oligomers (peptoids) are among the most promising candidates as potential anti-infectious agents due to their inherent ease of structural optimization. One of the approaches to rigidify the structure of peptoids is to introduce a covalent limitation and make them cyclic. In the present work we investigate the role of side chains of three cyclic peptoids in their interactions with model bacterial and cell membranes. The outer leaflets of Gram-positive and Gram-negative bacterial membranes were modeled with DPPG and Lipid A-Kdo2 monolayers, respectively. The lipid monolayers at the air-liquid interface were studied using constant-pressure insertion assays, epifluorescence microscopy (EFM), synchrotron X-ray reflectivity (XR) and grazing incident-angle diffraction (GID). We have found that both the electrostatic and hydrophobic forces play important roles in defining interactions of the peptoids with anionic lipid monolayers. Peptoids’ aryl side chains are responsible for the hydrophobic interactions and serve as determinants for the differential activity of the peptidomimetics. Our data suggest that bulkier groups promote an enhanced peptoid insertion into the bacterial membrane monolayer mimics. This agrees well with the higher antibacterial activity displayed by these compounds, indicating that bulkier groups, indeed, help peptoids in adopting rigid bioactive conformation.