Ca²⁺-triggered allosteric catalysts crosstalk with cellular redox systems through their foldase- and reductase-like...

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 Ca²⁺ concentrations, which is a key factor for maintenance of the redox status in cells. In the absence of Ca²⁺ or at low Ca²⁺ concentrations, the compounds were mostly inactive and hence did not affect cell viability. In contrast, under specific conditions with elevated cytosolic Ca²⁺ concentrations, the activated compounds resisted the redox imbalance induced by the reactive oxygen species generated by Ca²⁺-stimulated mitochondria. Smart catalysts that crosstalk with biological phenomena may provide a platform for new prodrug development guidelines.