Exploration of Backbone Space in Foldamers Containing α‐ and β‐Amino Acid Residues: Developing Protease‐Resistant Oligomers that Bind Tightly to the BH3‐Recognition Cleft of Bcl‐x L

Protein–protein interactions play crucial roles in cell‐signaling events and are often implicated in human disease. Molecules that bind tightly to functional protein‐surface sites and show high stability to degradative enzymes could be valuable pharmacological tools for dissection of cell‐signaling networks and might ultimately lead to therapeutic agents. We recently described oligomers containing both α‐ and β ‐amino acid residues that bind tightly to the BH3 recognition site of the anti‐apoptotic protein Bcl‐x L . The oligomers with highest affinity had a nine‐residue N‐terminal segment with a 1:1 α : β residue repeat and a six‐residue C‐terminal segment containing exclusively proteinogenic α ‐residues. The N‐terminal portions of such ( α / β + α )‐peptides are highly resistant to proteolysis, but the C‐terminal α ‐segments are susceptible. This study emerged from efforts to modify the α ‐segment in an ( α / β + α )‐peptide in a way that would diminish proteolytic degradation but retain high affinity for Bcl‐x L . Some of the oligomers reported here could prove useful in certain biological applications, particularly those for which extended incubation in a biological milieu is required.