Biophysical mimicry of lung surfactant protein B by random nylon-3 copolymers.
Non-natural oligomers have recently shown promise as functional analogues of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Here we present an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of beta-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers, inspired by the post-translational modifications found in SP-C, affords further improvements by reducing the percent surface area compression to reach low minimum surface tension. Cytotoxic effects of the copolymers are diminished relative to that of an SP-B-derived peptide and a peptoid-based mimic. The current study provides evidence that sequence-random copolymers can mimic the in vitro surface-active behavior of lung surfactant proteins in a mixed lipid film. These findings raise the possibility that random copolymers might be useful for developing a lung surfactant replacement, which is an attractive prospect given that such polymers are easier to prepare than are sequence-specific oligomers.
Dohm
Michelle T
MT
Department of Chemistry, Northwestern University, 2145 North Sheridan Road, Evanston, Illinois 60208-3100, USA.
Mowery
Brendan P
BP
Czyzewski
Ann M
AM
Stahl
Shannon S
SS
Gellman
Samuel H
SH
Barron
Annelise E
AE
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D055592:Biophysical Phenomena; D015195:Drug Design; D051379:Mice; D041681:NIH 3T3 Cells; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D019308:Palmitic Acid / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D037701:Pulmonary Surfactant-Associated Protein B / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013499:Surface Properties
D009757:Nylons; D010715:Phosphatidylglycerols; D037701:Pulmonary Surfactant-Associated Protein B; D015060:1,2-Dipalmitoylphosphatidylcholine; D019308:Palmitic Acid; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol