Recognition of ASF1 Using Hydrocarbon Constrained Peptides

Inhibition of the histone H3-ASF1 (anti-silencing function 1) protein-protein interaction (PPI) represents a potential approach for treatment of numerous cancers. As an α-helix mediated PPI, constraint of the key histone H3 helix (residues 118-135) represents a strategy through which chemical probes might be elaborated to test this hypothesis. In this work variant H3118-135 peptides bearing pentenyl glycine residues at 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 potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy-entropy compensation occurs.