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