Triangular prism-shaped β-peptoid helices as unique biomimetic scaffolds

Laursen, Jonas S.; Harris, Pernille; Fristrup, Peter; Olsen, Christian A.

doi:10.1038/ncomms8013

Cited by 75 publications

(119 citation statements)

References 51 publications

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“…The origin of ECCD is through‐space coupling of the naphthalene chromophores in a chiral environment. ECCD in this band has been observed in structured, naphthalene‐functionalized peptides and in β‐peptoids bearing the same ( S )‐1‐naphthylethyl side chains studied in organic solution, and suggested that the naphthalene rings are likewise regularly ordered in 1 ; this feature was consistent with the predicted amphiphilic helix structure of 1 , which would arrange all of the naphthalene side chains on one face of the helix. Interestingly, the split ECCD signal has not been observed for solutions of 1 or poly( N s1npe) peptoids studied in organic solution …”

Section: Resultssupporting

confidence: 75%

Solution effects on the self‐association of a water‐soluble peptoid

et al. 2018

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A desire to replicate the structural and functional complexity of proteins with structured, sequence‐specific oligomers motivates study of the structural features of water‐soluble peptoids (N‐substituted glycine oligomers). Understanding the molecular‐level details of peptoid self‐assembly in water is essential to advance peptoids' application as novel materials. Peptoid 1, an amphiphilic, putatively helical peptoid previously studied in our laboratory, shows evidence of self‐association in aqueous solution. In this work, we evaluate how changes to aqueous solution conditions influence the self‐association of 1. We report that changes to pH influence the fluorescence and CD spectroscopic features as well as the peptoid's interaction with a solvatochromic fluorophore and its apparent size as estimated by size exclusion chromatography. Addition of guanidine hydrochloride and ammonium sulfate also modulate spectroscopic features of the peptoid, its interaction with a solvatochromic fluorophore, and its elution in size exclusion chromatography. These data suggest that the ordering of the self‐assembly changes in response to pH and with solvent additives and is more ordered at higher pH and in the presence of guanidine hydrochloride. The deeper understanding of the self‐association of 1 afforded by these studies informs the design of new stimuli‐responsive peptoids with stable tertiary or quaternary structures.

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Section: Resultssupporting

confidence: 75%

Solution effects on the self‐association of a water‐soluble peptoid

et al. 2018

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“…The torsion angles of D-sulfono- γ -AA residues reasonably differ from those of α -helices, β -sheets, and the previously reported natural or synthetic peptides. 5b,6,14e,20 These unambiguous torsion angle data, along with the clear arrangement of side chain and hydrogen pattern, could shed light on the creation of either finite helical bundles in materials or the rational design of helical structure targeting membrane receptors or protein–protein interactions in the future.…”

Section: Resultsmentioning

confidence: 94%

Right-Handed Helical Foldamers Consisting of De Novo d-AApeptides

Teng

Cerrato

et al. 2017

J. Am. Chem. Soc.

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New types of foldamer scaffolds are formidably challenging to design and synthesize, yet highly desirable as structural mimics of peptides/proteins with a wide repertoire of functions. In particular, the development of peptidomimetic helical foldamers holds promise for new biomaterials, catalysts, and drug molecules. Unnatural L-sulfono-γ-AApeptides were recently developed and shown to have potential applications in both biomedical and material sciences. However, D-sulfono-γ-AApeptides, the enantiomers of L-sulfono-γ-AApeptides, have never been studied due to the lack of high-resolution three-dimensional structures to guide structure-based design. Herein, we report the first synthesis and X-ray crystal structures of a series of 2:1 L-amino acid/D-sulfono-γ-AApeptide hybrid foldamers, and elucidate their folded conformation at the atomic level. Single-crystal X-ray crystallography indicates that this class of oligomers folds into well-defined right-handed helices with unique helical parameters. The helical structures were consistent with data obtained from solution 2D NMR, CD studies, and molecular dynamics simulations. Our findings are expected to inspire the structure-based design of this type of unique folding biopolymers for biomaterials and biomedical applications.

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“…65 Moreover, fluorescence measurements at excitations from 230− 290 nm and recording of emission from 300−500 nm revealed no evidence for excimer effects caused by π−π interactions between naphthyl side chains. 65 The CD spectra of the N-1-phenylethyl series (19−23), on the other hand, did not provide any new insight compared to previous studies. 20,21 To provide further support for the existence of helical folding in solution, molecular dynamics simulations were performed on hexamer 29 (Figure 9b).…”

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

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Triangular prism-shaped β-peptoid helices as unique biomimetic scaffolds

Cited by 75 publications

References 51 publications

Solution effects on the self‐association of a water‐soluble peptoid

Solution effects on the self‐association of a water‐soluble peptoid

Right-Handed Helical Foldamers Consisting of De Novo d-AApeptides

β-Peptoid Foldamers at Last

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