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 <b>PhotoVDRM</b> 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 <b>PhotoVDRM</b> 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.
Authors
- Lourdes Muñoz (ORCID: https://orcid.org/0000-0001-6247-9334)
- Silvia Panarello
- Howard B. Broughton (ORCID: https://orcid.org/0000-0002-3293-3775)
- Paula Fernanda Pérez Rivero (ORCID: https://orcid.org/0000-0001-8195-1753)
- Carmen Serra
- Mingji Dai (ORCID: https://orcid.org/0000-0001-7956-6426)
- Francisco Ciruela (ORCID: https://orcid.org/0000-0003-0832-3739)
- Marc López‐Cano (ORCID: https://orcid.org/0000-0001-8885-3726)
- Elisabet Pérez‐Albaladejo (ORCID: https://orcid.org/0000-0002-1319-9552)
- Alfonso Espada (ORCID: https://orcid.org/0000-0002-8301-1201)
- Venkatesh Krishnan (ORCID: https://orcid.org/0000-0002-3295-6598)
- Joan Font (ORCID: https://orcid.org/0000-0001-8416-1909)
- Leticia Cano
- Donghui Ma (ORCID: https://orcid.org/0000-0002-0873-1305)
- Amadeu Llebaria (ORCID: https://orcid.org/0000-0002-8200-4827)
- Juanlo Catena (ORCID: https://orcid.org/0000-0002-2423-5926)
- Xianglin Yin (ORCID: https://orcid.org/0000-0003-4549-0827)
- Ana Trapero (ORCID: https://orcid.org/0000-0003-4526-7895)
- Pedro P. Irazoqui (ORCID: https://orcid.org/0000-0002-4791-4593)
- Xavier Rovira (ORCID: https://orcid.org/0000-0002-9764-9927)
- Hans Ajieren (ORCID: https://orcid.org/0000-0003-2308-0704)
- Paula Álvarez-Montoya
- Yanfei Li (ORCID: https://orcid.org/0000-0001-5566-7222)
- Sadid Khan (ORCID: https://orcid.org/0000-0002-8558-1152)
- Yanrong Li (ORCID: https://orcid.org/0000-0001-5841-9179)
- Jeffrey A. Dodge
Institutions
- Johns Hopkins University (US)
- Eli Lilly (United States) (US)
- Neurosciences Institute (US)
- Purdue University West Lafayette (US)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Institute of Advanced Chemistry of Catalonia (ES)
- Eli Lilly (Spain) (ES)
- Weldon City Schools (US)
- Chemical Synthesis Lab (SG)
Publication Details
- Journal
- ACS Central Science
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1021/acscentsci.5c00987
- Citations
- 1
- Primary Topic
- Photochromic and Fluorescence Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 0.52