Strategies for the intracellular synthesis of bioactive molecules in living cells

Drug discovery is often limited by the trade-off between potency and selectivity, which has led to the emergence of new therapeutic strategies that address this challenge. Intracellular synthesis is a novel drug-discovery approach in which active pharmacophores are assembled inside cells from inactive precursors. This approach has the potential to enhance selectivity, reduce off-target toxicity and enable enhanced spatiotemporal control of a drug's effect. In this Review, we highlight representative advances in the field, including transition-metal-catalysed reactions, artificial metalloenzymes, bioorthogonal metal-free reactions, light-promoted transformations and endogenous-stimulus-driven processes, with an emphasis on bond-forming reactions validated in living cells. We feature the types of bonds and products that can currently be formed in cells, their chemical requirements and the current limitations that must be addressed for intracellular synthesis to become a legitimate strategy in drug discovery and chemical biology.