Peptide Biomimicry: Structure-Activity Relationships of Peptoid Analogues of Lung Surfactant Protein C

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The adoption of surfactant replacement therapy (SRT) for the treatment of neonatal respiratory distress syndrome (nRDS) is one of the main contributors to the dramatic decline in infant mortality rates observed in the 1980s. Despite the significant efficacy of animal-derived surfactant preparations, there are still some concerns associated with their use including: possible spread of pathogenic material, batch-to-batch variability, high cost, and limited production potential. Therefore, research has been directed at the creation of synthetic surfactant preparations. Critical to this endeavor is the development of accurate analogues of the proteins of the lung surfactant system, SP-B and SP-C. Despite SP-C's relatively short sequence length and simple secondary structure, the predominately helical protein is extremely difficult to work with due to its extreme hydrophobicity and unstable secondary structure. One interesting approach that is particularly promising is the use of a poly-N-substituted glycines, or peptoids. Peptoids have close structural similarity to peptides and can be designed to form extraordinarily stable, helical structures that are resistant to protease degradation. These properties make peptoids especially promising candidates for the mimicry of peptides that rely on helical structure for their activity, such as SP-C. Here, detailed structure-activity relationships are reported for peptoid-based analogues of SP-C for use in a biomimetic SRT. Utilizing similar design strategies as those in peptide mimics of SP-C, a range of peptoid analogues was created with specific sequence alterations to better understand the key structural and molecular features necessary to recapitulate SP-C's unique biophysical activity. Specifically, the necessary structural requirements of the C-terminal, helical region and the unstructured, N-terminal region were investigated. Combining the information garnered from these studies, a peptoid-based analogue was created that mimics SP-C's extreme hydrophobicity, amphipathic patterning, and helical secondary structure, but because of its unique structure, overcomes the difficulties associated with the natural protein. When combined with a biomimetic phospholipid formulation, this analogue reproduces native SP-C's in vitro surface activity. With improved stability and greater production potential, peptoid SP-C mimics offer great potential not only to improve the treatment of nRDS, but also the treatment of other respiratory-related disorders.

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  • 10/08/2018
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