Stapled β‑Hairpins Featuring 4‑Mercaptoproline

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.