Constrained Peptides with Target‐Adapted Cross‐Links as Inhibitors of a Pathogenic Protein–Protein Interaction
Abstract
Bioactive conformations of peptides can be stabilized by macrocyclization, resulting in increased target affinity and activity. Such macrocyclic peptides proved useful as modulators of biological functions, in particular as inhibitors of protein–protein interactions (PPI). However, most peptide‐derived PPI inhibitors involve stabilized α‐helices, leaving a large number of secondary structures unaddressed. Herein, we present a rational approach towards stabilization of an irregular peptide structure, using hydrophobic cross‐links that replace residues crucially involved in target binding. The molecular basis of this interaction was elucidated by X‐ray crystallography and isothermal titration calorimetry. The resulting cross‐linked peptides inhibit the interaction between human adaptor protein 14‐3‐3 and virulence factor exoenzyme S. Taking into consideration that irregular peptide structures participate widely in PPIs, this approach provides access to novel peptide‐derived inhibitors.
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Self-citation
- Authors
- Glas, A., Bier, D., Hahne, G., Rademacher, C., Ottmann, C., & Grossmann, T. N.
- Affiliations
- Max Planck Society (DE)
- Max Planck Institute of Colloids and Interfaces (DE)
- Corresponding author
- Ottmann, Christian
- Grossmann, Tom N.
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2014-02-06
- Volume
- 53
- Issue
- 9
- Pages
- 2489-2493
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2154151379
- Cited by
- 145
- References
- 27
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 14 · 2023: 5 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 13 · 2017: 28 · 2016: 17 · 2015: 15 · 2014: 10
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion)
- TU/e Research Portal (submittedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- constrained peptides, protein-protein interaction inhibitors, exoenzyme S, virulence factors, macrocyclic peptides, peptide stabilization
- MeSH terms
- Amino Acid Sequence, Bacterial Toxins, Calorimetry, Humans, Models, Molecular, Peptides, Cyclic, Protein Binding, Pseudomonas aeruginosa, Pseudomonas Infections, Thermodynamics, Protein Structure, Secondary, Crystallography, X-Ray, ADP Ribose Transferases, Macrocyclic Compounds, 14-3-3 Proteins, Hydrophobic and Hydrophilic Interactions, Protein Interaction Maps
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