An in-tether sulfoxide chiral center influences the biophysical properties of the N-capped peptides

Li, Jingxu; Tian, Yuan; Wang, Dongyuan; Wu, Yujie; Ye, Xiyang; Li, Zigang

doi:10.1016/j.bmc.2016.11.042

Cited by 10 publications

(3 citation statements)

References 36 publications

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“…Thus, the PQPQ segment in both 16 and 17 is helical, chirally biased, and stabilized with respect to noncyclic sequence 14. Helix conformation control by stereocentres can be remote 46 . Here the nearest stereogenic centres are five atoms away from the foldamer helix at both C and N termini, which much contrasts with earlier examples of absolute handedness control 45 .…”

Section: Ribosomal Synthesis Of Macrocyclic Foldamer-peptide Hybridsmentioning

confidence: 99%

Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids

et al. 2018

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Translation, the mRNA-templated synthesis of peptides by the ribosome, can be manipulated to incorporate variants of the 20 cognate amino acids. Such approaches for expanding the range of chemical entities that can be produced by the ribosome may accelerate the discovery of molecules that can perform functions for which poorly folded, short peptidic sequences are ill suited. Here, we show that the ribosome tolerates some artificial helical aromatic oligomers, so-called foldamers. Using a flexible tRNA-acylation ribozyme-flexizyme-foldamers were attached to tRNA, and the resulting acylated tRNAs were delivered to the ribosome to initiate the synthesis of non-cyclic and cyclic foldamer-peptide hybrid molecules. Passing through the ribosome exit tunnel requires the foldamers to unfold. Yet foldamers encode sufficient folding information to influence the peptide structure once translation is completed. We also show that in cyclic hybrids, the foldamer portion can fold into a helix and force the peptide segment to adopt a constrained and stretched conformation.

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Section: Ribosomal Synthesis Of Macrocyclic Foldamer-peptide Hybridsmentioning

confidence: 99%

Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids

et al. 2018

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“…In 2016, Moore et al reported that an in-tether chiral center of stapled peptides influenced the secondary structures and binding affinities of the peptides . Meanwhile, we reported that a carbon chiral center precisely placed in a single-bonded tether dominates the backbone peptide’s helicity and biochemical and biophysical properties, including metabolic stability, cellular uptake, and target binding affinity. − This chirality-induced helicity strategy (CIH) has been expanded from a hydrocarbon chiral center to in-tether sulfur-based chiral centers such as sulfilimines and sulfoxides. − The CIH peptides provide a unique platform with which to evaluate solely conformational effects on the biophysical properties between peptide epimers. Precedent research indicated that amphipathic helices exhibit far greater cell permeability than similar sequences lacking helicity. , We also indicated that helical peptide epimers show significantly enhanced cellular uptakes compared with nonhelical epimers. , Notably, we also reported that the substituent at the in-tether chiral center significantly influences the cellular uptakes and target-binding affinities of the peptides …”

Section: Introductionmentioning

confidence: 99%

Dual In-Tether Chiral Centers Modulate Peptide Helicity

Sun

et al. 2017

Bioconjugate Chem.

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The facile chemical modification on the peptide cross-linking moiety is an important strategy for improving the physicochemical properties of a peptide. Herein, peptides were constrained into helical conformations via the synergistic effects of dual in-tether chiral centers. A pentapeptide minimalistic model was used to determine the correlation between the absolute configurations of the dual in-tether chiral centers and the secondary structures of the peptides. This strategy provides an on-tether modification site that does not interrupt the secondary structure of the peptide.

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“…The performance of the cyclic nine-residue scaffold (1Y)i nI dp rotein bindinga nd inhibition wass lightly superior to that of the linear 11-residue peptide ( 2). Moreover,t he former offers the possibility to better control the three-dimensionals tructure of the binding peptide, which will facilitate the design of Id protein inhibitors with enhanced protein-binding affinity in the future,e .g.,b yv arying the hydrophobic three-residuem otif F(i)ÀF(i + 3)ÀF(i + 6), by using alternative tethered peptides [59][60][61] or foldamers. [62,63]…”

Section: Discussionmentioning

confidence: 99%

Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide

et al. 2017

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The Id proteins (Id1-4) are cell-cycle regulators that play a key role during development, in cancer and vascular disorders. They contain a conserved helix-loop-helix (HLH) domain that folds into a parallel four-helix bundle upon self- or hetero-association with basic-HLH transcription factors. By using such protein-protein interactions, the Id proteins inhibit cell differentiation and promote cell-cycle progression. Accordingly, their supporting role in cancer has been convincingly demonstrated, which makes these proteins interesting therapeutic targets. Herein we present a short peptide containing an (i,i+4)-lactam bridge and a hydrophobic (Φ) three-residue motif Φ(i)-Φ(i+3)-Φ(i+6), which adopts a helical conformation in water, shows Id protein binding in the low-micromolar range, penetrates into breast (MCF-7 and T47D) and bladder (T24) cancer cells, accumulates in the nucleus, and decreases cell viability to ∼50 %. Thus, this cyclopeptide is a promising scaffold for the development of Id protein binders that impair cancer cell viability.

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An in-tether sulfoxide chiral center influences the biophysical properties of the N-capped peptides

Cited by 10 publications

References 36 publications

Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids

Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids

Dual In-Tether Chiral Centers Modulate Peptide Helicity

Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide

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