Peptoid drug discovery and optimization via surface X‐ray scattering

Abstract

Synthetic polymers mimicking antimicrobial peptides have drawn considerable interest as potential therapeutics. N‐substituted glycines, or peptoids, are recognized by their in vivo stability and ease of synthesis. Peptoids are thought to act primarily on the negatively charged lipids that are abundant in bacterial cell membranes. A mechanistic understanding of lipid–peptoid interaction at the molecular level will provide insights for rational design and optimization of peptoids. Here, we highlight recent studies that utilize synchrotron liquid surface X‐ray scattering to characterize the underlying peptoid interactions with bacterial and eukaryotic membranes. Cellular membranes are highly complex, and difficult to characterize at the molecular level. Model systems including Langmuir monolayers, are used in these studies to reduce system complexity. The general workflow of these systems and the corresponding data analysis techniques are presented alongside recent findings. These studies investigate the role of peptoid physicochemical characteristics on membrane activity. Specifically, the roles of cationic charge, conformational constraint via macrocyclization, and hydrophobicity are shown to correlate their membrane interactions to biological activities in vitro. These structure–activity relationships have led to new insights into the mechanism of action by peptoid antimicrobials, and suggest optimization strategies for future therapeutics based on peptoids.

Subphase Material Stabilizes Films of Pulmonary Surfactant

“…This continuous electron density was then fit to a simplified model of two slabs of discrete, uniform density (ρ) and length (l), bounded by the known densities of the subphase (water) and superphase (air). This approach has been recently applied for studying membrane interaction mechanisms by antimicrobial peptide mimics (41,(42)(43)(44), lipopolysaccharide permeability in Salmonella spp. (45,46), and surface catalysis (47).…”

Future prospects for Antimicrobial peptide development: peptidomimetics and antimicrobial combinations

“…Peptoids consist of oligomers of N-substituted glycine units and comprise a new class of biologically active peptidomimetics [11]. Their main site of action is the bacterial membrane, but the precise underlying mechanism remains unclear [11].…”

“…Peptoids consist of oligomers of N-substituted glycine units and comprise a new class of biologically active peptidomimetics [11]. Their main site of action is the bacterial membrane, but the precise underlying mechanism remains unclear [11]. An advantage of these molecules is their relatively long half-lives, as they are highly resistant to proteolytic degradation by trypsin and chemotrypsin and by other proteases as well [12].…”

The Best Peptidomimetic Strategies to Undercover Antibacterial Peptides

“…Peptoid optimization strategies in use are in vitro trial-and-error approaches [ 173 ], high-throughput ligand screening on large peptoid libraries [ 174 ], and computational approaches with prediction of peptoid efficacy in vitro [ 175 , 176 , 177 ]. The synchrotron liquid surface X-ray scattering studies of molecule structure–activity relationships have a new impact on studies of the mechanism of action by peptoid antimicrobials, and suggest optimization strategies for future therapeutics based on peptoids [ 178 ]. For instance, substitution of lysine to guanidine groups, increases the cationic charge and guides peptide–peptoid chimeras toward phosphatidylglycerol in bacterial membranes [ 179 ].…”