alpha/beta-Peptide foldamers targeting intracellular protein-protein interactions with activity in living cells
- Checco, JW; Lee, EF; Evangelista, M; Sleebs, NJ; Rogers, K; Pettikiriarachchi, A; Kershaw, NJ; Eddinger, GA; Belair, DG; Wilson, JL; Eller, CH; Raines, RT; Murphy, WL; Smith, BJ; Gellman, SH; Fairlie, WD;
Publication Year 2015-09-09, Volume 137, Issue #35, Page 11365-75
- Journal Title
- J Am Chem Soc
- Publication Type
- Journal Article
- Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-alpha-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 alpha- and beta-amino acid residues ("alpha/beta-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "alpha-peptides". This report documents an extension of the alpha/beta-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated alpha/beta-peptides based on a "stapled" Bim BH3 alpha-peptide, which contains a hydrocarbon cross-link to enhance alpha-helix stability. We show that a stapled alpha/beta-peptide can structurally and functionally mimic the parent stapled alpha-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the alpha/beta-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled alpha-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.
- WEHI Research Division(s)
- Systems Biology And Personalised Medicine; Structural Biology
- PubMed ID
- Link To PubMed Central Version
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-09-24 02:12:21Last Modified: 2016-10-12 02:49:12