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.