Close mimicry of lung surfactant protein B by "clicked" dimers of helical, cationic peptoids.

A family of peptoid dimers developed to mimic SP-B is presented, where two amphipathic, cationic helices are linked by an achiral octameric chain. SP-B is a vital therapeutic protein in lung surfactant replacement therapy, but its large-scale isolation or chemical synthesis is impractical. Enhanced biomimicry of SP-B's disulfide-bonded structure has been previously attempted via disulfide-mediated dimerization of SP-B(1-25) and other peptide mimics, which improved surface activity relative to the monomers. Herein, the effects of disulfide- or "click"-mediated (1,3-dipolar cycloaddition) dimerization, as well as linker chemistry, on the lipid-associated surfactant activity of a peptoid monomer are described. Results revealed that the 'clicked' peptoid dimer enhanced in vitro surface activity in a DPPC:POPG:PA lipid film relative to its disulfide-bonded and monomeric counterparts in both surface balance and pulsating bubble surfactometry studies. On the pulsating bubble surfactometer, the film containing the "clicked" peptoid dimer outperformed all presented peptoid monomers and dimers, and two SP-B derived peptides, attaining an adsorbed surface tension of 22 mN m(-1), and maximum and minimum cycling values of 42 mN m(-1) and near-zero, respectively. Copyright 2009 Wiley Periodicals, Inc.