Close mimicry of lung surfactant protein B by “clicked” dimers of helical, cationic peptoids

Dohm, Michelle T.; Seurynck-Servoss, Shannon L.; Seo, Jiwon; Zuckermann, Ronald N.; Barron, Annelise E.

doi:10.1002/bip.21309

Cited by 24 publications

(22 citation statements)

References 67 publications

(82 reference statements)

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“…While the disulfide linkage is strained, it can clearly permit dimer helical splays and surface dependent helix orientation in surfactant lipids, in agreement with our proposed model (6). Additionally, recent work on lung surfactant peptoids, or peptide mimics, showed that the linkage of monomers by a rigid triazole moiety to form a dimer enhanced in vitro surface activity in a lipid film relative to its monomeric counterparts (16). This further supports the idea that close proximity of the 2 peptoid helices serves to stabilize nanosilo formation.…”

Section: L343 Importance Of Sp-b Nh2-terminal Insertion Sequencesupporting

confidence: 84%

Functional importance of the NH₂-terminal insertion sequence of lung surfactant protein B

Frey

Pocivavsek

Waring

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lung surfactant protein B (SP-B) is required for proper surface activity of pulmonary surfactant. In model lung surfactant lipid systems composed of saturated and unsaturated lipids, the unsaturated lipids are removed from the film at high compression. It is thought that SP-B helps anchor these lipids closely to the monolayer in three-dimensional cylindrical structures termed "nanosilos" seen by atomic force microscopy imaging of deposited monolayers at high surface pressures. Here we explore the role of the SP-B NH2 terminus in the formation and stability of these cylindrical structures, specifically the distribution of lipid stack height, width, and density with four SP-B truncation peptides: SP-B 1-25, SP-B 9 -25, SP-B 11-25, and SP-B 1-25Nflex (prolines 2 and 4 substituted with alanine). The first nine amino acids, termed the insertion sequence and the interface seeking tryptophan residue 9, are shown to stabilize the formation of nanosilos while an increase in the insertion sequence flexibility (SP-B 1-25Nflex) may improve peptide functionality. This provides a functional understanding of the insertion sequence beyond anchoring the protein to the two-dimensional membrane lining the lung, as it also stabilizes formation of nanosilos, creating reversible repositories for fluid lipids at high compression. In lavaged, surfactant-deficient rats, instillation of a mixture of SP-B 1-25 (as a monomer or dimer) and synthetic lung lavage lipids quickly improved oxygenation and dynamic compliance, whereas SP-B 11-25 surfactants showed oxygenation and dynamic compliance values similar to that of lipids alone, demonstrating a positive correlation between formation of stable, but reversible, nanosilos and in vivo efficacy.

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Section: L343 Importance Of Sp-b Nh2-terminal Insertion Sequencesupporting

confidence: 84%

Functional importance of the NH₂-terminal insertion sequence of lung surfactant protein B

Frey

Pocivavsek

Waring

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The main approaches toward functional mimicry of surfactant proteins have involved peptide fragment synthesis, limited dimerization of SP-B and its analogues, recombinant protein expression, and more recently, peptoid synthesis, the subject of our recent contributions in this field 19-24. Although a recombinant form of SP-C is available,25 it is not palmitoylated, and no recombinant form of SP-B has yet been reported.…”

Section: Introductionmentioning

confidence: 99%

Biophysical Mimicry of Lung Surfactant Protein B by Random Nylon-3 Copolymers

et al. 2010

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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 β-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.

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“…The search for practical applications also began toward the development of reagents that could facilitate the cellular delivery of nucleic acids26, 63, 64 and serve as molecular recognition and capture reagents for diagnostic tests 65. We also established collaborations with other laboratories to explore the inhibition of protein–protein interactions,66, 67 the development of vaccines,68 antimicrobial peptoids,69 and lung surfactant mimetic70 peptoids. Research continues today in these areas as we address fundamental problems in nanoscience, self‐assembly, polymer physics, protein mimicry, and molecular recognition 71…”

Section: Protein Mimetic Polymersmentioning

confidence: 99%

Peptoid origins

Zuckermann¹

2010

Biopolymers

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196

192

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Peptoid oligomers were initially developed as part of a larger basic research effort to accelerate the drug-discovery process in the biotech/biopharma industry. Their ease of synthesis, stability, and structural similarity to polypeptides made them ideal candidates for the combinatorial discovery of novel peptidomimetic drug candidates. Diverse libraries of short peptoid oligomers provided one of the first demonstrations in the mid-1990s that high-affinity ligands to pharmaceutically relevant receptors could be discovered from combinatorial libraries of synthetic compounds. The solid-phase submonomer method of peptoid synthesis was so efficient and general that it soon became possible to explore the properties of longer polypeptoid chains in a variety of areas beyond drug discovery (e.g., diagnostics, drug delivery, and materials science). Exploration into protein-mimetic materials soon followed, with the fundamental goal of folding a non-natural sequence-specific heteropolymer into defined secondary or tertiary structures. This effort first yielded the peptoid helix and much later the peptoid sheet, both of which are secondary-structure mimetics that are close relatives to their natural counterparts. These crucial discoveries have brought us closer to building proteinlike structure and function from a non-natural polymer and have provided great insight into the rules governing polymer and protein folding. The accessibility of peptoid synthesis to chemists and nonchemists alike, along with a lack of information-rich non-natural polymers available to study, has led to a rapid growth in the field of peptoid science by many new investigators. This work provides an overview of the initial discovery and early developments in the peptoid field.

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Close mimicry of lung surfactant protein B by “clicked” dimers of helical, cationic peptoids

Cited by 24 publications

References 67 publications

Functional importance of the NH₂-terminal insertion sequence of lung surfactant protein B

Functional importance of the NH₂-terminal insertion sequence of lung surfactant protein B

Biophysical Mimicry of Lung Surfactant Protein B by Random Nylon-3 Copolymers

Peptoid origins

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Close mimicry of lung surfactant protein B by “clicked” dimers of helical, cationic peptoids

Cited by 24 publications

References 67 publications

Functional importance of the NH2-terminal insertion sequence of lung surfactant protein B

Functional importance of the NH2-terminal insertion sequence of lung surfactant protein B

Biophysical Mimicry of Lung Surfactant Protein B by Random Nylon-3 Copolymers

Peptoid origins

Contact Info

Product

Resources

About

Functional importance of the NH₂-terminal insertion sequence of lung surfactant protein B

Functional importance of the NH₂-terminal insertion sequence of lung surfactant protein B