Covalent Targeting\nof Histidine Residues with Aryl\nFluorosulfates: Application to Mcl‑1 BH3 Mimetics

Covalent drugs provide pharmacodynamic and pharmacokinetic\nadvantages\nover reversible agents. However, covalent strategies have been developed\nmostly to target cysteine (Cys) residues, which are rarely found in\nbinding sites. Among other nucleophilic residues that could be in\nprinciple used for the design of covalent drugs, histidine (His) has\nnot been given proper attention despite being in principle an attractive\nresidue to pursue but underexplored. Aryl fluorosulfates, a mild electrophile\nthat is very stable in biological media, have been recently identified\nas possible electrophiles to react with the side chains of Lys; however,\nlimited studies are available on aryl fluorosulfates’ ability\nto target His residues. We demonstrate that proper incorporation of\nan aryl fluorosulfate juxtaposing the electrophile with a His residue\ncan be used to afford rapid optimizations of His-covalent agents.\nAs an application, we report on His-covalent BH3 mimetics targeting\nHis224 of Mcl-1.