Structural Superimposition

Abstact

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 alpha-helix and the H4 beta-strand epitopes. Systematic optimization of linker geometry, beta-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.