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

ABSTRACT: We report progress toward a general strategy for mimicking the recognition properties of specific ?-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both ?- and ?-amino acid residues, with the density of the ? subunits low enough that an ?-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 ? residues can be superior to flexible ? residues in terms of maximizing ?/?-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 ? 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 ? 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 ?/?-peptides containing ring-preorganized ? residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize ?-helical partners.

SUBMITTER: Peterson-Kaufman KJ 

PROVIDER: S-EPMC4666709 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature