Ca-triggered allosteric catalysts crosstalk with cellular redox systems through their foldase- and reductase-like activities.

Effective chemical catalysts can artificially control intracellular metabolism. However, in conventional catalytic chemistry, activity and cytotoxicity have a trade-off relationship; thus, driving catalysts in living cells remains challenging. To overcome this critical issue at the interface between catalytic chemistry and biology, we developed cell-driven allosteric catalysts that exert catalytic activity at specific times. The synthesized allosteric redox catalysts up- and downregulated their foldase- and antioxidase-like activities in response to varying Ca concentrations, which is a key factor for maintenance of the redox status in cells. In the absence of Ca or at low Ca concentrations, the compounds were mostly inactive and hence did not affect cell viability. In contrast, under specific conditions with elevated cytosolic Ca concentrations, the activated compounds resisted the redox imbalance induced by the reactive oxygen species generated by Ca-stimulated mitochondria. Smart catalysts that crosstalk with biological phenomena may provide a platform for new prodrug development guidelines.