Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide.
Antineoplastic Agents
/ chemistry
Cell Line, Tumor
Cell Membrane Permeability
/ drug effects
Cell Proliferation
/ drug effects
Cell-Penetrating Peptides
/ chemistry
Humans
MCF-7 Cells
Molecular Dynamics Simulation
Peptides
/ chemistry
Peptides, Cyclic
/ chemistry
Proof of Concept Study
Protein Interaction Maps
/ drug effects
Proto-Oncogene Proteins c-mdm2
/ metabolism
TCF Transcription Factors
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
beta Catenin
/ metabolism
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
27 11 2019
27 11 2019
Historique:
pubmed:
29
10
2019
medline:
15
7
2020
entrez:
29
10
2019
Statut:
ppublish
Résumé
Stapled peptides recapitulate the binding affinity and specificity of α-helices in proteins, resist proteolytic degradation, and may provide a novel modality against challenging drug targets such as protein-protein interactions. However, most of the stapled peptides have limited cell permeability or are impermeable to the cell membrane. We show herein that stapled peptides can be rendered highly cell-permeable by conjugating a cyclic cell-penetrating peptide to their N-terminus, C-terminus, or stapling unit. Application of this strategy to two previously reported membrane-impermeable peptidyl inhibitors against the MDM2/p53 and β-catenin/TCF interactions resulted in the generation of potent proof-of-concept antiproliferative agents against key therapeutic targets.
Identifiants
pubmed: 31657556
doi: 10.1021/acs.jmedchem.9b00456
pmc: PMC7291828
mid: NIHMS1595618
doi:
Substances chimiques
Antineoplastic Agents
0
CTNNB1 protein, human
0
Cell-Penetrating Peptides
0
Peptides
0
Peptides, Cyclic
0
TCF Transcription Factors
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
beta Catenin
0
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
10098-10107Subventions
Organisme : NCI NIH HHS
ID : R01 CA234124
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122459
Pays : United States
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