Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.
Aldehydes
/ chemistry
Amines
/ chemistry
Amino Acid Sequence
Catalytic Domain
Crystallography, X-Ray
Cyanides
/ chemistry
Fluorescence Polarization
Magnetic Resonance Spectroscopy
Models, Molecular
Peptides
/ chemistry
Protein Binding
Protein Conformation
Proto-Oncogene Proteins c-mdm2
/ chemistry
Tumor Suppressor Protein p53
/ chemistry
HSQC NMR
Ugi reaction
cancer
p53-MDM2/X
stapled peptides
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
23 03 2020
23 03 2020
Historique:
received:
18
12
2019
pubmed:
17
1
2020
medline:
18
3
2021
entrez:
17
1
2020
Statut:
ppublish
Résumé
Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.
Identifiants
pubmed: 31944488
doi: 10.1002/anie.201916257
doi:
Substances chimiques
Aldehydes
0
Amines
0
Cyanides
0
Peptides
0
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5235-5241Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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