Light-Regulated Agonists Spatiotemporally Activating the Vitamin D Receptor Mitigate Psoriasis-like Inflammation in Mice without Inducing Hypercalcemia.

Vitamin D receptor (VDR) activation has demonstrated beneficial effects on psoriasis. However, its crucial role in calcium metabolism limits clinical applications due to the risk of health-threatening dysregulation in serum calcium. In the present study, we have designed, synthesized, and biologically tested highly potent light-controllable VDR agonists containing a photoswitchable azobenzene moiety in the drug scaffold. The optimized molecule PhotoVDRM is inactive in the dark and can be selectively activated with light using specific wavelengths, including nonphototoxic visible blue light and UVB that is currently used in skin treatments. We used a modified hydrogen/deuterium exchange method to identify the binding site and study VDR dynamics upon ligand binding. Importantly, testing PhotoVDRM in a psoriasis mouse model demonstrates that it can spatiotemporally activate VDR in localized diseased areas. Strikingly, this targeted activation results in a robust therapeutic effect without systemic hypercalcemia, thereby addressing at the preclinical level a major historic impediment to VDR agonist treatments in clinical trials. This photopharmacology-based strategy enables the discovery of innovative targeted medicines using light-controlled agonists to spatiotemporally activate the VDR at pathological sites.