De novo α/β-peptidomimetics effectively mimic transcription factors by targeting the CBP KIX domain

Protein-protein interactions (PPIs) regulating gene expression in the nucleus are crucial therapeutic targets, yet challenging to address. Effective targeting requires molecules that can interact with large protein surfaces while being small enough to traverse the nuclear pore. Current strategies often overlook critical properties like solubility, charge, or local flexibility. Peptidomimetics offer a promising solution, particularly for their ability to be finely tuned, addressing the need for small, specific modulators of nuclear processes.

Researchers employed a de novo design strategy using α/β-peptidomimetics to target the KIX domain of p300/CBP coactivator proteins as a model system. This approach allowed for modular optimization of hot-spot, solvent-exposed, and structure-inducing residues to tune affinity and binding-site selectivity. They exploited multivalency by creating dimers from initial hits. Both static libraries and template-directed dynamic covalent chemistry were utilized to screen multivalent ligands, aiming to mimic native interaction partners closely.

The de novo design strategy using α/β-peptidomimetics successfully enabled modular optimization of hot-spot, solvent-exposed, and structure-inducing residues, thereby effectively tuning both affinity and binding-site selectivity for the CBP KIX domain. This modularity allowed for precise control over the interaction profile. The researchers demonstrated that their approach could generate manageable-sized, soluble libraries of these peptidomimetics.

The design approach allowed for the creation of multivalent ligands (dimers) that closely mimic the native interaction partners of the KIX domain, enhancing binding and selectivity. Both static libraries and template-directed dynamic covalent chemistry proved effective in facilitating the screening and identification of these multivalent ligands. This represents a promising approach for developing novel ligands against proteins characterized by high plasticity and multivalent interactions, offering a pathway to target challenging nuclear protein-protein interactions.