(172e) Peptoid Analogues of Lung Surfactant Protein C

Lung surfactant protein C (SP-C) is a hydrophobic lipopeptide that is crucial for the dynamic behavior of lung surfactant (LS). It's inclusion, along with SP-B, in animal-based surfactant replacement therapies for the treatment of neonatal respiratory distress syndrome has been demonstrated to be more clinically effective than synthetic surfactant preparations, which lack the hydrophobic proteins. However, due to concerns with animal-derived surfactants, recent investigation has focused on the creation of synthetic analogues of the LS proteins. Given SP-C's extreme hydrophobicity and propensity to misfold and aggregate, creating an accurate mimic of the full lipopeptide is extraordinarily challenging. One interesting approach, which overcomes these difficulties, is the use of poly-N-substituted glycines, or “peptoids” for this objective. Peptoids have close structural similarity to peptides, form stable helices, resist protease degradation, and are less prone to immune system recognition than peptides. These properties make peptoids an excellent candidate for the mimicry of natural molecules that rely on helical structure for proper bioactivity such as the hydrophobic proteins of LS.

We have synthesized, purified, and performed in vitro testing of a range of peptoid-based mimics that differ in their helicitly, sequence length, and N-terminal alkylation. All mimics were designed to capture the amphipathic patterning and highly helical nature of the natural protein and were studied in order to develop detailed structure-function relationships of peptoid analogues of SP-C. Circular dichroism spectroscopy gives evidence the peptoid-based mimics of SP-C form stable, helical structures in solution. Pulsating bubble surfactometry, Langmuir-Wilhelmy surface balance, and fluorescence microscopy experiments demonstrate that the peptoid-based analogues exhibit favorable surface activities and film morphologies when combined with a biomimetic phospholipid formulation while overcoming the difficulties associated with the natural protein. These experiments also provide evidence that N-terminal alkylation of the peptoid analogues substantially improves the surface activity, closely approximating the natural lipopeptide. These results are promising for the development of a synthetic, biomimetic, peptoid-based LS formulation.