Histone chaperones assist in the assembly and disassembly of the histones around which the DNA of our chromosomes is wrapped.

For the past 20 years, researchers from the I2BC at the CEA-Joliot have been studying the histone chaperone ASF1, whose concentration within cells increases very strongly in certain tumors. Conversely, the decrease in its concentration dramatically slows down cell proliferation.

ASF1 is therefore a therapeutic target in the fight against cancers, particularly in very aggressive breast cancers. To block the action of this chaperone protein, CEA-Joliot researchers are developing a strategy based on the design of peptides – molecules made up of short chains of amino acids – that associate with ASF1 instead of histones and thus inhibit its action.

The team created peptides showing a potential inhibitory effect on tumor growth in a study combining structural, computational and biochemical approaches. However, these first designed peptides were rapidly degraded by protease enzymes and thus too fragile for use in therapy.

The researchers then began imagined new compounds from synthetic building blocks in order to make them more resistant to proteases without modifying their capacity to inhibit ASF1. For this, they used artificial polymers known as foldamers that are capable of forming well-defined structures, similarly to peptides.

The modeling work has made it possible to design a new inhibitor of ASF1 in the form of a foldamer/peptide hybrid molecule. Its resistance to degradation in human plasma is far superior to that of the related peptide. In addition, its structure displays a remarkable plasticity allowing the foldamer to adapt its conformation to the surface of ASF1 and maintain the same binding interface as the previously designed peptide inhibitor.

This hybrid molecule still needs to be optimized to reach the ASF1 chaperone protein within the cell, so as to effectively inhibit its action.