We propose to develop a novel class of biomaterials called """"""""polypeptoids,"""""""" or poly-N-substituted glycines, and to apply them to a specific biomedical problem: the need for more effective synthetic, functional mimics of the human lung surfactant proteins SP-B and SP-C. Lung surfactant (LS) is a surface-active material that coats the internal surfaces of healthy mammalian lungs and enables breathing, by reducing the surface tension on the alveolar surfaces. LS is composed of 95 percent surface-active lipids and 5 percent surfactant-specific proteins; both lipid and protein fractions are necessary for its functioning. Two of these surfactant-specific proteins, SP- B, and SP-C, are especially surface-active and are critical for the proper biophysical functioning of LS in vitro and in vivo. SP-B and SP-C are both small, helical, amphipathic proteins (79 and 35 amino acids, respectively); essentially, just peptides. Premature infants born before about 30 weeks of gestation are born with immature lungs lacking surfactant, and require the delivery of an exogenous lung surfactant replacement at birth to enable mechanical ventilation. At present, the most efficacious LS replacement formulations are animal- derived, and therefore raise concerns about their level of purity, their consistency of formulation, and their potential for pathogen transmission, as do any medicines sourced directly from animals. While synthetic LS replacements do exist, they do not work as well as animal- derived surfactant replacements, primarily because these formulations lack good functional replacements for SP-B and SP-C proteins. We propose to develop functional mimics of SP-B and SP-C based on poly-N-substituted glycines, which are sequence- specific heteropolymers synthesized in a similar manner to synthetic polypeptides, by a facile, automated solid-phase protocol. Peptoids offer the advantage s of protease- resistance, biomimetic helical secondary structure, low immunogenicity, and low cost. Peptoid-based SP-mimics will be synthesized, purified, and their secondary structure and biophysical surface activities will be analyzed in vitro circular dichroism spectroscopy and by equilibrium and dynamic surfactometry. The feasibility of these novel SP- mimics is demonstrated in preliminary work. Promising formulations will be tested in vivo by a collaborator.
| Czyzewski, Ann M; McCaig, Lynda M; Dohm, Michelle T et al. (2018) Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins. Sci Rep 8:6795 |
| Chongsiriwatana, Nathaniel P; Lin, Jennifer S; Kapoor, Rinki et al. (2017) Intracellular biomass flocculation as a key mechanism of rapid bacterial killing by cationic, amphipathic antimicrobial peptides and peptoids. Sci Rep 7:16718 |
| Brown, Nathan J; Dohm, Michelle T; de la Serna, Jorge Bernardino et al. (2011) Biomimetic N-terminal alkylation of peptoid analogues of surfactant protein C. Biophys J 101:1076-85 |
| Chongsiriwatana, Nathaniel P; Wetzler, Modi; Barron, Annelise E (2011) Functional synergy between antimicrobial peptoids and peptides against Gram-negative bacteria. Antimicrob Agents Chemother 55:5399-402 |
| Dohm, Michelle T; Kapoor, Rinki; Barron, Annelise E (2011) Peptoids: bio-inspired polymers as potential pharmaceuticals. Curr Pharm Des 17:2732-47 |
| Chongsiriwatana, Nathaniel P; Miller, Tyler M; Wetzler, Modi et al. (2011) Short alkylated peptoid mimics of antimicrobial lipopeptides. Antimicrob Agents Chemother 55:417-20 |
| Dohm, Michelle T; Mowery, Brendan P; Czyzewski, Ann M et al. (2010) Biophysical mimicry of lung surfactant protein B by random nylon-3 copolymers. J Am Chem Soc 132:7957-67 |
| Chongsiriwatana, Nathaniel P; Barron, Annelise E (2010) Comparing bacterial membrane interactions of antimicrobial peptides and their mimics. Methods Mol Biol 618:171-82 |
| Dohm, Michelle T; Brown, Nathan J; Seurynck-Servoss, Shannon L et al. (2010) Mimicking SP-C palmitoylation on a peptoid-based SP-B analogue markedly improves surface activity. Biochim Biophys Acta 1798:1663-78 |
| Dohm, Michelle T; Seurynck-Servoss, Shannon L; Seo, Jiwon et al. (2009) Close mimicry of lung surfactant protein B by ""clicked"" dimers of helical, cationic peptoids. Biopolymers 92:538-53 |
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