Turn up the Vitamin D Receptor─Not the Calcium! Photoswitchable Vitamin D Agonists for Psoriasis

Abstract

P hotopharmacology is an emerging interdisciplinary field at the interface of pharmacology and photo-chemistry that takes advantage of molecular transducers capable of undergoing reversible isomerization, i.e., photoswitches. By incorporating photoswitches into bio-active molecules, light can exert spatiotemporal control over compound activity. In this context, azobenzene-based switches are currently the most commonly employed, due to their synthetic accessibility as well as suitable photo-chemical properties. Importantly, the photoisomerization of azobenzene from the thermodynamically stable trans isomer to the metastable cis one entails distinct geometry (transition from a planar one to a more compact, globular one; decrease in the end-to-end distance from ∼9 Å to ∼6 Å) and electronics (increase in the dipole moment from ∼0D to ∼3D) that turn azobenzene into highly effective scaffolds for the photocontrol of biological systems. 1,2 From a therapeutic perspective, an ideal light-operated drug should be inactive in the dark and become active only under irradiation, limiting its action to the illuminated targeted area in order to avoid off-target effects. Unfortunately, conventional azobenzene-based photodrugs often display suboptimal profiles because, typically, the thermally stable trans isomer is the active form ("trans-on"). 3 To address this limitation, we could either use the sign inversion approach using cyclic diazocines or develop cis-on molecules with the ability to interact with the receptor only in the cis configuration (cisoid geometry), resembling the active agonists, whereas the trans flat structure is more distant from the active ligand geometries. In this issue of ACS Central Science, Rovira, Krishnan, Llebaria, and their colleagues introduce an innovative strategy to treat psoriasis by developing cis-on photo-switchable agonists of the vitamin D receptor (VDR), which enables a light-controlled localized and time-limited treatment of psoriasis in preclinical mouse models without inducing the undesirable side effect of hypercalcemia (Figure 1). 4