The vitamin D receptor (VDR), a member of the nuclear hormone receptor superfamily, is a ligand-dependent transcription factor which regulates cell proliferation, cell differentiation, and calcium homeostasis. VDR can be found in the cytosol and the nuclei, where it binds vitamin D metabolites. The most active vitamin D metabolite is 1,25-dihydroxyvitamin D3 (calcitriol). Upon binding to calcitriol, VDR localizes to the nuclei where it interacts with coregulators and DNA. Universal tool compounds to further elucidate the expression and localization of VDR are not available; therefore, we are working towards the development of a new VDR ligand that can easily be traced in vitro and in vivo. Molecular modeling was conducted for a number of intrinsically fluorescent compounds that mimic the secosteroidal structure of calcitriol, which has in turn provided a foundation for novel ligand syntheses. Preliminary binding and cytotoxicity assays have been completed for select synthetic ligands, along with a VDR-mediated transcription assay to determine agonistic/antagonistic ability. Future research endeavors include the improvement of synthetic ligand-VDR binding and minimization of cellular toxicity. VDR has been identified as an important pharmaceutical target for the treatment of metabolic disorders, skin diseases, cancer, autoimmune diseases, and cardiovascular diseases. A tight-binding, intrinsically fluorescent ligand would allow for the creation of a new in vitro assay, thus aiding the development of future small-molecule pharmaceuticals that target the VDR ligand binding domain. Furthermore, we hope to use the fluorescence properties of this compound to evaluate the in vivo distribution of VDR. Unlike immunohistochemistry, utilization of this compound would enable us to determine the physiological distribution of VDR in live cells and whole animals, ultimately providing further information on the complete role VDR plays within the cell.

Development of small-molecule-based probes for the vitamin D receptor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.