Biophysical studies on hydrocarbon constrained peptides reveal induced fit binding and enthalpy–entropy compensation on target protein recognition.

An aromatic oligoamide foldamer acts as an α-helix mimetic and binds to the RNase S-protein resulting in restoration of its catalytic function.

Inhibiting the histone H3–ASF1 (anti‐silencing function 1) protein–protein interaction (PPI) represents a potential approach for treating numerous cancers. As an α‐helix‐mediated PPI, constraining the key histone H3 helix (residues 118–135) is a strategy through which chemical probes might be elaborated to test this hypothesis. In this work, variant H3 118–135 peptides bearing pentenylglycine residues at the i and i +4 positions were constrained by olefin metathesis. Biophysical analyses revealed that promotion of a bioactive helical conformation depends on the position at which the constraint is introduced, but that the potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy–entropy compensation occurs.