Stapled β-Hairpins Featuring 4-Mercaptoproline
Jennifer R. Pace, Bryan J. Lampkin, Charles Abakah, Adam Moyer, J. Miao, Kirsten Deprey, Robert A. Cerulli, Yu‐Shan Lin, James Baleja, David Baker, Joshua A. Kritzer
Abstract
Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer examples of similarly constrained scaffolds for other secondary structures. Here, we used a novel computational strategy to identify an optimal staple for antiparallel β-strands, and then we incorporated that staple within a β-hairpin peptide. The hairpin uses 4-mercaptoproline as a novel staple component, which contributes to a unique, kinked structure. The stapled hairpins show a high degree of structure in aqueous solution, excellent resistance to degradation in cell lysates, and cytosolic penetration at micromolar concentrations. They also overlay with a unique subset of kinked hairpin motifs at protein-protein interaction interfaces. Thus, these scaffolds represent promising starting points for developing inhibitors of cellular protein-protein interactions.