Passive Membrane Permeability of Sizable Acyclic β‑Hairpin Peptides

The recent shift toward increasingly larger drug modalities has created a significant demand for novel classes of compounds with high membrane permeability that can inhibit intracellular protein–protein interactions (PPIs). While major advances have been made in the design of cell-permeable helices, stapled β-sheets, and cyclic peptides, the development of large acyclic β-hairpins lags far behind. Therefore, we investigated a series of 26 β-hairpins (MW > 1.6 kDa) belonging to a chemical space far beyond the Lipinski “rule of five” (fbRo5) and showed that, in addition to their innate plasticity, the lipophilicity of these peptides (log D7.4 ≈ 0 ± 0.7) can be tuned to drastically improve the balance between aqueous solubility and passive membrane permeability.