Downsizing the Histone H3–H4 Quaternary Structure Into Foldamer Mimetics Yields High‐Affinity and Cell‐Permeable Ligands of ASF1

Mimicking complex protein–protein interfaces with small, well‐defined molecular scaffolds remains a major challenge in chemical biology. Here, we report a foldamer‐based downsizing strategy that compresses the quaternary architecture of the histone H3–H4 dimer into compact peptide‐oligourea hybrids acting as high‐affinity ligands of the histone chaperone Anti‐Silencing Function 1 (ASF1). Guided by multiple high‐resolution co‐crystal structures, we designed a series of foldamer mimetics that accurately reproduce both the H3 α‐helix and the H4 β‐strand epitopes. Systematic optimization of linker geometry, β‐strand mimicry, formal charge, and selective backbone N‐methylation yielded highly stable ligands with nanomolar affinities, enhanced proteolytic resistance, and robust cytosolic penetration. Notably, the optimized constructs and their N‐methylated analogues recapitulate the binding mode of the native H3–H4 dimer on ASF1 with high fidelity and engage endogenous ASF1 in cell extracts, demonstrating effective intracellular target recognition. Together, these results show that peptide‐oligourea foldamers can reproduce the structural features of a protein quaternary structure surface, combining high affinity, high stability and cell permeability.