Peptidomimetic spreading agents for a novel synthetic and bioavailable lung surfactant replacement: Design, synthesis, and biophysical characterization

A current challenge in bioengineering is the exploitation of non-natural, sequence-specific, and length-controlled oligomers for biomedical applications. Poly-N-substituted glycines or “peptoids” are a unique class of bioinspired, sequence-specific polymers that offer protease resistance and low immunogenicity. Despite the lack of backbone chirality and their inability to form intrachain hydrogen bonds, peptoids can adopt stable helices with the incorporation of α-chiral, sterically hindered side chains. Systematic study of homooligomers of α-chiral aromatic side chains shows that the secondary structure of peptoid helices becomes length-independent for chains longer than 12 residues. Detailed, comparative study of short, heterooligomer peptoids with mixed chiral and α-chiral side chains reveals that a composition of at least 50% α-chiral aromatic side chains, the placement of an α-chiral monomer on the carboxy terminus, and the periodic placement of α-chiral aromatic monomers are important for the formation of stable helical structures. Investigation of the effects of side chain chemistry on peptoid helices reveals that three different classes of peptoids adopt the same type of polyproline type-I-like helices.; Better understanding of the design criteria for peptoid helix formation enables the utilization of peptoids for the creation of novel therapeutic agents. An important biomaterial that is necessary for normal breathing is lung surfactant (LS), a complex mixture of lipids and proteins. We have successfully designed, synthesized, and characterized helical peptoid mimics of the bioactive domain of SP-C to serve as spreading agents for a functional biomimetic LS replacement. In vitro studies show the promise of biomimetic LS replacements containing peptoid-based SP-C mimics. We have studied different SP-C mimics and showed that good surface activity is dependent on the presence of a helical, hydrophobic C-terminus that is of some minimal chain length, but otherwise is insensitive to small changes in the length and side chain chemistry of the helix. We also studied and showed the effects of lipid and surfactant protein mimic components of the LS formulation on performance. In this doctoral work, we have demonstrated successful bioengineering mimicry of protein domains with peptoids. This is an exciting finding that has implications for future applications of peptoids and other non-natural oligomers as therapeutic agents.