Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling

Wendt, Mathias; Bellavita, Rosa; Gerber, Alan; Efrém, Nina‐Louisa; Ramshorst, Thirza van; Pearce, Nicholas M.; Davey, Paul; Everard, Isabel; Vázquez–Chantada, Mercedes; Chiarparin, Elisabetta; Grieco, Paolo; Hennig, Sven; Grossmann, Tom N.

doi:10.1002/ange.202102082

Cited by 8 publications

(7 citation statements)

References 71 publications

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“…25−29 Recently, Grossman and co-workers described E-cadherin β-sheet mimics to engage β-catenin. 30 Our efforts complement this work. We begin from a β-strand of a distinct protein partner (Tcf4) and focus on capturing this strand as part of a β-hairpin scaffold.…”

Section: ■ Introductionmentioning

confidence: 75%

Covalent and Noncovalent Targeting of the Tcf4/β-Catenin Strand Interface with β-Hairpin Mimics

Ghosh

Ramoni²

2021

ACS Chem. Biol.

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β-Strands are a fundamental component of protein structure, and these extended peptide regions serve as binding epitopes for numerous protein−protein complexes. However, synthetic mimics that capture the conformation of these epitopes and inhibit selected protein−protein interactions are rare. Here we describe covalent and noncovalent β-hairpin mimics of an extended strand region mediating the Tcf4/β-catenin interaction. Our efforts afford a rationally designed lead for an underexplored region of βcatenin, which has been the subject of numerous ligand discovery campaigns.

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Section: ■ Introductionmentioning

confidence: 75%

Covalent and Noncovalent Targeting of the Tcf4/β-Catenin Strand Interface with β-Hairpin Mimics

Ghosh

Ramoni²

2021

ACS Chem. Biol.

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“…Helicity values were calculated using the CDNN software tool (spectra range for calc. : 195–260 nm, , accessed on 1 January 2021) developed by G. Böhm [ 39 , 40 ].…”

Section: Methodsmentioning

confidence: 99%

Stapling of Peptides Potentiates the Antibiotic Treatment of Acinetobacter baumannii In Vivo

et al. 2022

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The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity.

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“…Atomic-level characterisation of peptide:target complexes has revealed the impact of a variety of stapling chemistries on the binding modes of stapled peptides. [11], [32], [33], [34] Understanding the conformational changes induced by the staple moiety can benefit the design of new binders. While it has been shown that DVT can link i, i+7 residues on α-helical MDM2-binding peptides, the conformation of the linker and its effect on the helix geometry are unclear.…”

Section: Structural Characterisation Of Cysteine-stapled Brc8-2 Repeatsmentioning

confidence: 99%

“…[9], [10] Recently, alternative structural elements, such as βhairpins and loops have been successfully utilised for stapling. [11], [12] Stapling of the nucleophilic side chain of cysteines has been explored as an attractive alternative to RCM, as it avoids the use of non-natural amino acids and metal catalysts. [13] Stapling of cysteines can be done in mild, biocompatible conditions, allowing it to be used in the context of affinity selections of combinatorial libraries.…”

Section: Introductionmentioning

confidence: 99%

A Recombinant Approach For Stapled Peptide Discovery Yields Inhibitors of the RAD51 Recombinase

Pantelejevs¹,

Zuazua-Villar

Koczy³

et al. 2023

Preprint

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Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry, as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment.

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Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling

Cited by 8 publications

References 71 publications

Covalent and Noncovalent Targeting of the Tcf4/β-Catenin Strand Interface with β-Hairpin Mimics

Covalent and Noncovalent Targeting of the Tcf4/β-Catenin Strand Interface with β-Hairpin Mimics

Stapling of Peptides Potentiates the Antibiotic Treatment of Acinetobacter baumannii In Vivo

A Recombinant Approach For Stapled Peptide Discovery Yields Inhibitors of the RAD51 Recombinase

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