Tuning Histone Site Selectivity in the Nucleosome with Organometallic Agents

Histone alterations are increasingly recognized as oncogenic drivers, yet the chromatin drug portfolio is largely limited to DNA-targeting agents and inhibitors of chromatin-modifying proteins. Because nucleosomes play a foundational role in genomic regulation while presenting chemically diverse protein surfaces, principles of site discrimination could open up new possibilities for therapeutic interventions. Here, we show that ruthenium- and osmium-based compounds can be tuned to selectively bind specific histone sites in the nucleosome. The identity of the metal cation and non-leaving ligands dictates adduct stability and whether complexes target exposed electronegative patches or internal crevices, with steric accessibility, hydrophobic/van der Waals complementarity, and ligand lability governing site specificity. Our findings yield design rules for selective engagement of histones, suggesting that organometallic compounds can be rationally developed to target defined chromatin features and expand the scope of epigenetic therapeutics.