J Am Chem Soc. 2015 Sep 9;137(35):11365-75.
Checco JW, Lee EF1,2, Evangelista M1, Sleebs NJ1, Rogers K1,2, Pettikiriarachchi A1, Kershaw NJ1,2, Eddinger GA, Belair DG, Wilson JL, Eller CH, Raines RT,Murphy WL, Smith BJ3, Gellman SH, Fairlie WD1,2.
- 1The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.
- 2Department of Medical Biology, University of Melbourne , Parkville, Victoria 3010, Australia.
- 3Department of Chemistry and Physics, La Trobe Institute of Molecular Science , Melbourne, Victoria 3086, Australia.
Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-α-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 α- and β-amino acid residues ("α/β-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "α-peptides". This report documents an extension of the α/β-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated α/β-peptides based on a "stapled" Bim BH3 α-peptide, which contains a hydrocarbon cross-link to enhance α-helix stability. We show that a stapled α/β-peptide can structurally and functionally mimic the parent stapled α-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the α/β-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled α-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.