Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α‑Helix Mimics

• Published in: ACS chemical biology 2015-07, Vol.10 (7), p.1667-1675
• Main Authors: Peterson-Kaufman, Kimberly J, Haase, Holly S, Boersma, Melissa D, Lee, Erinna F, Fairlie, W. Douglas, Gellman, Samuel H
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis; bcl-X Protein - chemistry; bcl-X Protein - metabolism; Cell Line; Humans; Mice; Molecular Docking Simulation; Molecular Sequence Data; Myeloid Cell Leukemia Sequence 1 Protein - chemistry; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.5b00109

We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subunits low enough that an α-helix-like conformation can be adopted but high enough to interfere with protease activity. Previous studies with a different protein-recognition system that suggested ring-constrained β residues can be superior to flexible β residues in terms of maximizing α/β-peptide affinity for a targeted protein surface. Here, we use mimicry of the 18-residue Bim BH3 domain to expand the scope of this strategy. Two significant advances have been achieved. First, we have developed and validated a new ring-constrained β residue that bears an acidic side chain, which complements previously known analogues that are either hydrophobic or basic. Second, we have discovered that placing cyclic β residues at sites that make direct contact with partner proteins can lead to substantial discrimination between structurally homologous binding partners, the proteins Bcl-xL and Mcl-1. Overall, this study helps to establish that α/β-peptides containing ring-preorganized β residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize α-helical partners.