Designable Nanozymes for Site‐Selective Amide/Ester Hydrolysis

Site selectivity in catalysis requires the catalyst to recognize not only the targeted reactive group on the substrate but also its structural context. Such selectivity is vital to many biological catalytic reactions, including those found in the posttranslational modification of proteins. Although site-selective catalysts would enable precise transformations of molecules, polymers, and materials, no general strategy exists for the rational design of site-selective catalysts. We here report nanozymes with tunable substrate-binding sites and strategically positioned catalytic groups. A zinc cofactor, together with proximal acidic and basic groups, activates water for nucleophilic attack on the bound ester or amide. The size/shape of the active site and the position of the catalytic groups are tuned rationally through molecular imprinting, using modularly synthesized acylthiourea templates. These nanozymes enable programmable site-selective hydrolysis of esters and amides, independent of the intrinsic reactivities of the competing functional groups.