Weak backbone CH<scp>⋯</scp>OC and side chain tBu<scp>⋯</scp>tBu London interactions help promote helix folding of achiral NtBu peptoids

Angelici, Gaetano; Bhattacharjee, Nicholus; Roy, Olivier; Faure, Sophie; Didierjean, Claude; Jouffret, Laurent; Jolibois, Franck; Perrin, Luc; Taillefumier, Claude

doi:10.1039/c6cc00375c

Cited by 33 publications

(80 citation statements)

References 21 publications

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“…An analysis of the ϕ and ψ angles present in published peptoid structures (41 crystal structures, 5 NMR structures, 132 total dihedral combinations, Supporting Information Table S1) reveal that trans‐ and cis ‐amides show similar preferences for ϕ and ψ combinations, with trans ‐amide and cis ‐amide residues primarily occupying two main regions that span across the bottom and top edges of the Ramachandran plot (ϕ ≈ 70° and −70° and ψ ≈ 180° and −180°, Figure ). Replotting these data to represent ϕ and ψ from 0° to 360° (adding 360° to ϕ and ψ values below 0°, Figure C,F) shows that the preferred dihedrals lay in the same low‐energy regions for trans and cis disarcosine calculatations, with regions centered around (70°, 180°) and (290°,180°) (Figure C,F).…”

Section: The Ramachandran Plotmentioning

confidence: 99%

Stereochemistry of polypeptoid chain configurations

et al. 2019

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Like polypeptides, peptoids, or N‐substituted glycine oligomers, have intrinsic conformational preferences due to their amide backbones and close spacing of side chain substituents. However, the conformations that peptoids adopt are distinct from polypeptides due to several structural differences: the peptoid backbone is composed of tertiary amide bonds that have trans and cis conformers similar in energy, they lack a backbone hydrogen bond donor, and have an N‐substituent. To better understand how these differences manifest in actual peptoid structures, we analyzed 46 high quality, experimentally determined peptoid structures reported in the literature to extract their backbone conformational preferences. One hundred thirty‐two monomer dihedral angle pairs were compared to the calculated energy landscape for the peptoid Ramachandran plot, and were found to fall within the expected minima. Interestingly, only two regions of the backbone dihedral angles ϕ and ψ were found to be populated that are mirror images of each other. Furthermore, these two conformers are present in both cis and trans forms. Thus, there are four primary conformers that are sufficient to describe almost all known backbone conformations for peptoid oligomers, despite conformational constraints imposed by a variety of side chains, macrocyclization, or crystal packing forces. Because these conformers are predominant in peptoid structure, and are distinct from those found in protein secondary structures, we propose a simple naming system to aid in the description and classification of peptoid structure.

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Section: The Ramachandran Plotmentioning

confidence: 99%

Stereochemistry of polypeptoid chain configurations

et al. 2019

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“…The cis/trans ratio of the terminal acetamide was determined for all the trimer peptoids 4 ‐ 9 by 1 H NMR integration of singlets corresponding to the acetyl CH 3 protons (Figure ). According to previous studies, the protons of trans peptoid acetamides are deshielded which results in a chemical shift of ˃2 ppm. On the contrary, it was observed that the protons of cis acetamides display a chemical shift of <2 ppm.…”

Section: Resultsmentioning

confidence: 86%

“…The coupling of these two trimers using FDPP as coupling reagent in the presence of DBU as base, yielded the hexamer 18 in 44% yield. The use of a two‐step procedure involving the corresponding activated pentafluorophenyl ester intermediate instead proved less efficient. Indeed, only 12% of hexamer 18 was formed and nearly 50% of the trimer block amine 15 was recovered after purification of the crude product.…”

Section: Resultsmentioning

confidence: 99%

“…Among the cis ‐inducing peptoid side chains, the tert ‐butyl side chain is unique as it induces complete cis conformation via steric effects, regardless of the nature of the solvent (Figure A) . In addition, despite the absence of chirality, a network of weak interactions such as intramolecular CO( i ) … HC( i − n) ( n = 1, 2, or 3) hydrogen bonds and i / i + 3 t Bu … t Bu London interactions help the folding of Nt Bu peptoid oligomers into the PPI‐like helical conformation (Figure B) …”

Section: Introductionmentioning

confidence: 99%

“…(A) Peptoid oligomer carrying the tert ‐butyl side chain; (B) X‐ray structure of the pentamer Ac‐( Nt Bu) 5 ‐OBn …”

Section: Introductionmentioning

confidence: 99%

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NCα‐gem‐dimethylated peptoid side chains: A novel approach for structural control and peptide sequence mimetics

et al. 2019

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The design of linear peptoid oligomers adopting well‐defined secondary structures while mimicking defined peptide primary sequences is a major challenge in the context of drug discovery. To this end, chemists have developed cis‐inducing peptoid side chains to build robust polyproline type I helices. However, the number of efficient examples remains scarce and chemical diversity accessible through the use of these side chains is limited. Herein, we introduce an array of NCα‐gem‐dimethylated peptoid residues mimicking proteinogenic amino acids. Submonomer synthesis and block‐coupling approaches were explored to access heterooligomers incorporating these novel types of side chains. NMR studies of monomer and trimer models showed that the NCα‐gem‐dimethylated groups exert complete cis control on the backbone amide conformation. Lastly, a preliminary molecular modeling study gave an insight into the preferred orientation of the substituents of the NCα‐gem‐dimethyl side chains relative to the peptoid backbone.

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Strategies to Control the Cis‐Trans Isomerization of Peptoid Amide Bonds

Kalita

Sahariah

Mookerjee

et al. 2022

Chemistry An Asian Journal

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Peptoids are oligomers of N‐substituted glycine units. They structurally resemble peptides but, unlike natural peptides, the side chains of peptoids are present on the amide nitrogen atoms instead of the α‐carbons. The N‐substitution improves cell‐permeability of peptoids and enhance their proteolytic stability over natural peptides. Therefore, peptoids are ideal peptidomimetic candidates for drug discovery, especially for intracellular targets. Unfortunately, most peptoid ligands discovered so far possess moderate affinity towards their biological targets. The moderate affinity of peptoids for biomacromolecules is linked to their conformational flexibility, which causes substantial entropic loss during the peptoid‐biomacromolecule binding process. The conformational flexibility of peptoids is caused by the lack of backbone chirality, absence of hydrogen bond donors (NH) in their backbone to form CO⋅⋅⋅HN hydrogen bonds and the facile cis‐trans isomerization of their tertiary amide bonds. In recent years, many investigators have shown that the incorporation of specific side chains with unique steric and stereoelectronic features can favourably shift the cis‐trans equilibria of peptoids towards one of the two isomeric forms. Such strategies are helpful to design homogenous peptoid oligomers having well defined secondary structures. Herein, we discuss the strategies developed over the years to control the cis‐trans isomerization of peptoid amide bonds.

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Weak backbone CH⋯OC and side chain tBu⋯tBu London interactions help promote helix folding of achiral NtBu peptoids

Cited by 33 publications

References 21 publications

Stereochemistry of polypeptoid chain configurations

Stereochemistry of polypeptoid chain configurations

NCα‐gem‐dimethylated peptoid side chains: A novel approach for structural control and peptide sequence mimetics

Strategies to Control the Cis‐Trans Isomerization of Peptoid Amide Bonds

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