Effects of Hydrophobic Helix Length and Side Chain Chemistry on Biomimicry in Peptoid Analogues of SP-C

Brown, Nathan; Wu, Cindy W.; Seurynck-Servoss, Shannon L.; Barron, Annelise E.

doi:10.1021/bi7021975

Cited by 46 publications

(48 citation statements)

References 60 publications

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“…While inclusion of dB1 , mB2 , dB2 , and dB4 led to little to no improvement in adsorptive properties relative to B1 , both mB3 and dB3 enabled a more rapid adsorption of the lipid film, and created surface films that reached a lower γ eq than was seen with the other monomers and disulfide-based dimers. It has been previously shown in peptoid mimics of SP-B that inclusion of aliphatic residues, and in general, an increased proportion of hydrophobicity, facilitated significantly more rapid adsorption to the a/l interface42,44. Of the disulfide-based dimers, dB3 resulted in the lowest γ max and a slightly lower % compression, where the N -propyl chains may once again promote better association with the lipid acyl chains of the dynamic film.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2009

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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-B1-25 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.

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Section: Discussionmentioning

confidence: 92%

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

et al. 2009

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“…4 The breadth of peptoid function continues to expand, 5 highlighted by recent investigations that have yielded potent antimicrobial agents, 6,7 modulators of protein-protein interactions, 8-11 RNA-binding agents, 12-15 lung surfactants, 16,17 anti-biofouling agents, 18 asymmetric catalysts, 19 and self-assembled nano-structures. 20,21 Peptoids can be synthesized in a straightforward modular fashion 22 and possess desirable characteristics such as proteolytic stability 23 and increased cellular permeability relative to their α-peptide equivalents.…”

Section: Introductionmentioning

confidence: 99%

Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains

et al. 2011

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Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homooligomers by X-ray crystallography, NMR and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 Å. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide Kcis/trans values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homooligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.

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“…Most of the applications of peptoids consist of mimics of a -helices, in two particular areas: antimicrobial agents, where peptoids have been used to mimic a -helical, membrane disruptive peptides (Patch and Barron 2003;Shin et al 2007 ;Gorske and Blackwell 2006 ;Fowler et al 2008 ) , and as mimics of the two hydrophobic a -helical proteins in lung surfactant, SP-B and SP-C (Seurynck- Servoss et al 2006;Brown et al 2008 ) . In the fi eld of protein aggregation, the use of peptoids has been limited to analogues of amylin (islet amyloid polypeptide, IAPP) residues 21-30 (-SNNFGAILSS-).…”

Section: Peptoids and Modifi Cations Of The A -Carbonmentioning

confidence: 99%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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Effects of Hydrophobic Helix Length and Side Chain Chemistry on Biomimicry in Peptoid Analogues of SP-C

Cited by 46 publications

References 60 publications

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

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

Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

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