Strengthening Peptoid Helicity through Sequence Site-Specific Positioning of Amide <i>cis</i>-Inducing <i>Nt</i>Bu Monomers

Rzeigui, Maha; Traı̈kia, Mounir; Jouffret, Laurent; Kriznik, Alexandre; Jameleddine, Khiari; Roy, Olivier; Taillefumier, Claude

doi:10.1021/acs.joc.9b02916

Cited by 19 publications

(18 citation statements)

References 45 publications

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“…For example, N-substituted monomers bearing benzylic-type Nα-chiral groups including the phenylethyl [19][20][21], naphthylethyl [17,[22][23][24], and triazolium groups [25][26][27], alkyl ammonium [28], tert-butyl/α,α-gem-dimethyl [29], or fluorinated groups [30] will preferentially form cis-amides (Figure 1A). Peptoid helicity modulation has also been investigated through specific placement of chiral and achiral monomers [31,32]. Comparatively fewer N-functional monomers capable of promoting trans-peptoid amides were designed.…”

Section: Introductionmentioning

confidence: 99%

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

Pypec¹,

Jouffret²,

Taillefumier³

et al. 2022

Beilstein J. Org. Chem.

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The synthesis and conformational analysis of the first series of peptoid oligomers composed of consecutive N-(alkylamino)glycine units is investigated. We demonstrate that N-(methylamino)glycine homooligomers can be readily synthesized in solution using N-Boc-N-methylhydrazine as a peptoid submonomer and stepwise or segment coupling methodologies. Their structures were analyzed in solution by 1D and 2D NMR, in the solid state by X-ray crystallography (dimer 2), and implicit solvent QM geometry optimizations. N-(Methylamino)peptoids were found to preferentially adopt trans amide bonds with the side chain N–H bonds oriented approximately perpendicular to the amide plane. This orientation is conducive to local backbone stabilization through intra-residue hydrogen bonds but also to intermolecular associations. The high capacity of N-(methylamino)peptoids to establish intermolecular hydrogen bonds was notably deduced from pronounced concentration-dependent N–H chemical shift variation in 1H NMR and the antiparallel arrangement of mirror image molecules held together via two hydrogen bonds in the crystal lattice of dimer 2.

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Section: Introductionmentioning

confidence: 99%

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

Pypec¹,

Jouffret²,

Taillefumier³

et al. 2022

Beilstein J. Org. Chem.

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“…As protein–protein interactions mediate virtually all biological processes and represent unparalleled potential targets for novel therapeutics, tremendous efforts have been undertaken in recent years toward effective PPI modulations. − Peptides and peptidomimetics offer exceptional prospects of mimicking protein domains essential for PPIs, with the latter offering unique advantages with respect to stability and bioavailability. , Some notable peptidomimetics developed so far include peptoids, , β-peptides, , α/β-peptides, − azapeptides, , oligoureas, , and others. − α/β-Peptides derived from Z domain peptides were particularly shown to bind to VEGFR and to have more resistance to proteases than α-peptides …”

Section: Introductionmentioning

confidence: 99%

Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor

Abdulkadir

Jiang

et al. 2021

J. Am. Chem. Soc.

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Angiogenesis, formation of new blood vessels from the existing vascular network, is a hallmark of cancer cells that leads to tumor vascular proliferation and metastasis. This process is mediated through the binding interaction of VEGF-A with VEGF receptors. However, the balance between pro-angiogenic and anti-angiogenic effect after ligand binding yet remains elusive and is therefore challenging to manipulate. To interrogate this interaction, herein we designed a few sulfono-γ-AA peptide based helical peptidomimetics that could effectively mimic a key binding interface on VEGF (helix-α1) for VEGFR recognition. Intriguingly, although both sulfono-γ-AA peptide sequences V2 and V3 bound to VEGF receptors tightly, in vitro angiogenesis assays demonstrated that V3 potently inhibited angiogenesis, whereas V2 activated angiogenesis effectively instead. Our findings suggested that this distinct modulation of angiogenesis might be due to the result of selective binding of V2 to VEGFR-1 and V3 to VEGFR-2, respectively. These molecules thus provide us a key to switch the angiogenic signaling, a biological process that balances the effects of pro-angiogenic and anti-angiogenic factors, where imbalances lead to several diseases including cancer. In addition, both V2 and V3 exhibited remarkable stability toward proteolytic hydrolysis, suggesting that V2 and V3 are promising therapeutic agents for the intervention of disease conditions arising due to angiogenic imbalances and could also be used as novel molecular switching probes to interrogate the mechanism of VEGFR signaling. The findings also further demonstrated the potential of sulfono-γ-AA peptides to mimic the α-helical domain for protein recognition and modulation of protein–protein interactions.

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“…Inspired by detailed studies of the trans-cis-amide equilibria of proline residues, [35][36][37][38] efforts have also been directed towards the development of methods to control these ratios in and -peptoids. [39][40][41][42][43][44][45][46][47][48][49] Still, only a limited number of examples of high-resolution structures of folded oligomers have been solved, [50][51][52][53][54][55][56][57][58] underlining the continued challenge of achieving structure-based design of oligomeric peptoids. We reported the N-(S)-1-(1-naphthyl)ethyl (Ns1npe, 1) side chain to promote formation of triangular prism-shaped -peptoid helical structure of oligomer 2, 31,53 and recently elaborated upon this highly cis-amide bond-inducing side chain to incorporate longer hydrocarbons (3) and amino groups.…”

Section: Introductionmentioning

confidence: 99%

“…Peptoids of both the α - and β-type share the tertiary amide bond structural element, which gives rise to isomerization between transoid and cisoid conformations, termed trans -amide and cis -amide bonds, respectively. Inspired by detailed studies of the trans–cis -amide equilibria of proline residues, − efforts have also been directed toward the development of methods to control these ratios in α- and β-peptoids. − Still, only a limited number of examples of high-resolution structures of folded oligomers have been solved, − underlining the continued challenge of achieving the structure-based design of oligomeric peptoids. We reported the N -( S )-1-(1-naphthyl)ethyl ( N s1npe, 1 ) side chain to promote the formation of a triangular prism-shaped β-peptoid helical structure of oligomer 2 , , and recently elaborated upon this highly cis -amide bond-inducing side chain to incorporate longer hydrocarbons ( 3 ) and amino groups .…”

Section: Introductionmentioning

confidence: 99%

Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding

et al. 2020

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We report the synthesis of a series of bis-functionalized -peptoid oligomers of the hexamer length. This was achieved by synthesizing and incorporating protected amino-or azido-functionalized chiral building blocks into precursor oligomers by a trimer segment coupling strategy. The resulting hexamers were readily elaborated to provide target compounds displaying amino groups, carboxy groups, hydroxy groups, or triazolo-pyridines, which should enable metal ion binding. Analysis of the novel hexamers by CD spectroscopy and HSQC NMR spectroscopy revealed robust helical folding propensity in acetonitrile. CD analysis showed solvent-dependent degree of helical content in the structural ensembles when adding different ratios of protic solvents including aqueous buffer. These studies were enabled by the substantial increase in solubility compared to previously analyzed -peptoid oligomers. This also allowed for investigation of the effect of pH on folding propensity of the amino-and carboxy-functionalized oligomers, respectively. Interestingly, we could demonstrate a reversible effect of sequentially adding acid and base, resulting in a switching between compositions of folded ensembles with varying helical content. We envision that the present discoveries can form the basis for the development of functional peptidomimetic materials responsive to external stimuli.

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Strengthening Peptoid Helicity through Sequence Site-Specific Positioning of Amide cis-Inducing NtBu Monomers

Cited by 19 publications

References 45 publications

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor

Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding

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