期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 53, 期 9, 页码 2489-2493出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201310082
关键词
cyclic peptides; hydrophobic cross-links; protein-protein interactions; Pseudomonas aeruginosa; ring-closing metathesis
资金
- Fonds der Chemischen Industrie
- German Research Foundation (DFG) [RA1944/2-1, GR3592/2-1]
- AstraZeneca
- Bayer CropScience
- Bayer HealthCare
- Boehringer Ingelheim
- Merck KGaA
- Max Planck Society
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 -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 exoenzymeS. Taking into consideration that irregular peptide structures participate widely in PPIs, this approach provides access to novel peptide-derived inhibitors.
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