Photoswitchable RNA Degraders for Spatiotemporal Activation of Host-Directed Antivirals in Mammalian Cells

Strategies to develop broad-spectrum antivirals are highly sought after. A promising modern approach includes recruitment of host proteins as a means of activating immune responses that target multiple virus families. Host-directed therapies require a balance of antiviral effects and immunopathology. Herein, a known RNase L ligand was retrofitted with a hemithioindigo photoswitch to obtain a novel light-activatable pyrazol-hemithioindigo pharmacophore. This newly developed class of RNase L ligands allows spatiotemporal control of RNA degradation with isolated enzyme as well as in human cancer cells and virus infected cells. This work showcases the implementation of photopharmacology to elicit antiviral effects as potential strategy to limit off-site toxicity stemming from RNA degradation. The designed photoswitches provide a tool to study exogenous, conditional activation of RNase L for the development of broad-spectrum antivirals.