title: α/β-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-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.
authors: James W
authors: JW
authors: Checco
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne , Parkville, Victoria 3010, Australia.
authors: Erinna F
authors: EF
authors: Lee
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.
authors: Marco
authors: M
authors: Evangelista
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.
authors: Nerida J
authors: NJ
authors: Sleebs
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne , Parkville, Victoria 3010, Australia.
authors: Kelly
authors: K
authors: Rogers
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.
authors: Anne
authors: A
authors: Pettikiriarachchi
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne , Parkville, Victoria 3010, Australia.
authors: Nadia J
authors: NJ
authors: Kershaw
authors: Geoffrey A
authors: GA
authors: Eddinger
authors: David G
authors: DG
authors: Belair
authors: Julia L
authors: JL
authors: Wilson
authors: Chelcie H
authors: CH
authors: Eller
authors: Ronald T
authors: RT
authors: Raines
authors: William L
authors: WL
authors: Murphy
authors: Department of Chemistry and Physics, La Trobe Institute of Molecular Science , Melbourne, Victoria 3086, Australia.
authors: Brian J
authors: BJ
authors: Smith
authors: Samuel H
authors: SH
authors: Gellman
authors: The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne , Parkville, Victoria 3010, Australia.
authors: W Douglas
authors: WD
authors: Fairlie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry; D000072224:Bcl-2-Like Protein 11; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000737:chemistry
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D057846:Cell-Penetrating Peptides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D045304:Cytochromes c; D010447:Peptide Hydrolases