?/?-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.

ABSTRACT: Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-?-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both ?- and ?-amino acid residues ("?/?-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "?-peptides". This report documents an extension of the ?/?-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated ?/?-peptides based on a "stapled" Bim BH3 ?-peptide, which contains a hydrocarbon cross-link to enhance ?-helix stability. We show that a stapled ?/?-peptide can structurally and functionally mimic the parent stapled ?-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the ?/?-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled ?-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain cross-linking to produce synergistic benefits.

SUBMITTER: Checco JW 

PROVIDER: S-EPMC4687753 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature