Light‐Regulated Stapled Peptides to Inhibit Protein–Protein Interactions Involved in Clathrin‐Mediated Endocytosis

Nevola, Laura; Martín‐Quirós, Andrés; Eckelt, Kay; Camarero, Núria; Tosi, Sébastien; Llobet, Artur; Giralt, Ernest; Gorostiza, Pau

doi:10.1002/anie.201303324

Cited by 88 publications

(98 citation statements)

References 31 publications

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“…31 Allemann and co-workers have applied i,i + 4/7/11 azobenzene stapling to peptides which bind the oncogenic protein Bcl-xL, 32 finding that switching of helicity correlates with the ability of the peptide to bind its protein target in vitro. The biological application of photoswitchable linkers has been further advanced by Nevola et al, 33 who have created stapled peptides for regulating clathrin-mediated endocytosis (CME) by targeting the beta-adaptin subunit of the AP2 complex, a key player in the CME process. The optimised stapled peptides were shown to bind their protein target in vitro using a fluorescence polarisation assay, with the expected reversible changes in affinity upon photoswitching.…”

Section: Photoswitchable Linkersmentioning

confidence: 99%

Peptide stapling techniques based on different macrocyclisation chemistries

et al. 2015

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Peptide stapling is a strategy for constraining short peptides typically in an alpha-helical conformation. Stapling is carried out by covalently linking the side-chains of two amino acids, thereby forming a peptide macrocycle. There is an expanding repertoire of stapling techniques based on different macrocyclisation chemistries. In this tutorial review, we categorise and analyse key examples of peptide stapling in terms of their synthesis and applicability to biological systems.

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Section: Photoswitchable Linkersmentioning

confidence: 99%

Peptide stapling techniques based on different macrocyclisation chemistries

et al. 2015

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“…[20–22] Combining a two-component approach with click chemistry enables easy access to peptides bearing different functional staples. Whilst we appended cell-permeabilizing motifs to the staple, others have used a two-component approach to create photoswitchable,[23] reversible,[24] and dynamic linkers. [25]…”

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confidence: 99%

Double Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides

et al. 2015

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Peptide stapling is a method for designing macrocyclic alpha-helical inhibitors of protein-protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide-alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. α-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications.

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“…In the i , i +7 setup, the α-helical conformation was shown to be more pronounced with the cis -azobenzene moiety, whereas the trans configuration led to increased α-helicity for i , i +11 cross-linking. [214] These azobenzene-cross-linked peptides proved useful as switchable PPI inhibitors. [214]…”

Section: Methodsmentioning

confidence: 99%

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

et al. 2015

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Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.

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Light‐Regulated Stapled Peptides to Inhibit Protein–Protein Interactions Involved in Clathrin‐Mediated Endocytosis

Cited by 88 publications

References 31 publications

Peptide stapling techniques based on different macrocyclisation chemistries

Peptide stapling techniques based on different macrocyclisation chemistries

Double Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

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