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Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide.

ABSTRACT: Stapled peptides recapitulate the binding affinity and specificity of ?-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 ?-catenin/TCF interactions resulted in the generation of potent proof-of-concept antiproliferative agents against key therapeutic targets.

SUBMITTER: Dougherty PG

PROVIDER: S-EPMC7291828 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide.

Dougherty Patrick G PG Wen Jin J Pan Xiaoyan X Koley Amritendu A Ren Jian-Guo JG Sahni Ashweta A Basu Ruchira R Salim Heba H Appiah Kubi George G Qian Ziqing Z Pei Dehua D

Journal of medicinal chemistry 20191108 22

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 s ...[more]

PMID: 31657556

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