Reaction hijacking of enzymes to generate potent therapeutic modulators in situ

Abstract Enzymes play critical roles in all aspects of biology, making them important targets for therapeutics in infectious diseases and cancer. In addition to the well-known and exploited competitive and suicide inhibitors, reaction hijacking compounds are emerging as important inhibitors with therapeutic potential. We review how hijacking inhibitors exploit the enzyme's catalytic cycle to generate potent modulators in situ. The target enzyme catalyses the formation of a covalent adduct between a substrate-mimicking hijacker and a co-substrate or cofactor. Susceptible enzymes include members of the superfamily of adenylate-forming enzymes, NAD⁺-metabolising enzymes, and a range of cofactor-dependent enzymes. Hijacking compounds are usually unreactive until activated by the target enzyme, affording good selectivity and potency, as well as favourable physiochemical properties and synthetic tractability.