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

Author(s): 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;
Details: Publication Year 2015-09-09,Volume 137,Issue #35,Page 11365-75
Journal Title: J Am Chem Soc
Publication Type: Journal Article
Abstract: 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.
Publisher: ACS
Research Division(s): Systems Biology And Personalised Medicine; Structural Biology
PubMed ID: 26317395
Link To PubMed Central Version: https://www-ncbi-nlm-nih-gov/pmc/articles/PMC4687753/
Publisher's Version: https://doi.org/10.1021/jacs.5b05896
NHMRC Grants: NHMRC/1041936, NHMRC/1024620,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-09-24 02:12:21

Last Modified: 2016-10-12 02:49:12