Recognition of ASF1 by Using Hydrocarbon-Constrained Peptides

Area of Science:

• Biochemistry
• Chemical Biology
• Cancer Research

Background:

• The histone H3-ASF1 protein-protein interaction (PPI) is a potential therapeutic target for various cancers.
• This interaction is mediated by an alpha-helix, making the histone H3 helix (residues 118-135) a key target for chemical probes.

Purpose of the Study:

• To design and synthesize constrained histone H3 peptides to investigate their effect on the H3-ASF1 PPI.
• To explore the relationship between helical conformation, constraint position, and binding affinity to ASF1.

Main Methods:

• Synthesis of variant H3(118-135) peptides incorporating pentenylglycine residues.
• Cyclization of peptides using olefin metathesis to introduce conformational constraints.
• Biophysical analyses to assess helical conformation and binding potency to ASF1.

Main Results:

• The position of the conformational constraint influenced the promotion of a bioactive helical conformation.
• Peptide binding potency towards ASF1 remained unaffected by the introduction of the constraint.
• Enthalpy-entropy compensation was observed in the binding interactions.

Conclusions:

• Conformational constraints can modulate the helical structure of histone H3 peptides.
• Constraint placement is critical for achieving desired helical conformations, but does not alter ASF1 binding potency.
• The findings provide a basis for developing chemical probes targeting the H3-ASF1 interaction for cancer therapy.