Dual-Capped Helical Interface Mimics

Disruption of protein–protein interactions is
medicinally
important. Interface helices may be mimicked in helical probes featuring
enhanced rigidities, binding to protein targets, stabilities in serum,
and cell uptake. This form of mimicry is dominated by stapling between
side chains of helical residues: there has been less progress on helical N-caps, and there were no generalizable C-caps. Conversely, in natural proteins, helicities are stabilized
and terminated by C- and N-caps
but not staples. Bicyclic caps previously introduced by us enable
interface helical mimicry featuring rigid synthetic caps at both termini
in this work. An unambiguously helical dual-capped system proved to
be conformationally stable, binding cyclins A and E, and showed impressive
cellular uptake. In addition, the dual-capped mimic was completely
resistant to proteolysis in serum over an extended period when compared
with “gold standard” hydrocarbon-stapled controls. Dual-capped
peptidomimetics are a new, generalizable paradigm for helical interface
probe design.