Editorial [ Vitamin D and its Binding Protein: Challenges and Opportunities for Drug Research Guest Editor: Dr. Hubert Maehr ]

The recognition that Vitamin D exerts its activity through a nuclear mechanism led to the discovery of the binding protein, the vitamin-D receptor or VDR. As a consequence of this agonist binding in the ligand-binding domain (LBD), the VDR changes its topology and, after translocation from the cytoplasm to the nucleus, permits the VDR to function as a ligandactivated transcription factor by virtue of its association with the response elements (VDREs) in some 50 vitamin-D regulated genes. This binding phenomenon to DNA at the VDRE sites is a complex process and occurs by heterodimerization with the retinoid X-receptor (RXR) and recruitment of a complex machinery of co-modulators and co-activators. The hormonally active form of vitamin D, 1,25-dihydroxy vitamin D3 (1,25(OH)2D3), is produced by a sequence of steps commencing with a photochemically induced conrotatory, electrocyclic ring opening of 7-dehydrocholesterol in the skin leading to previtamin D3 which is subject to a thermal, antarafacial [1,7]-hydrogen shift, followed by 25-hydroxylation in the liver to generate 25(OH)D3, and 1α-hydroxylation, preferentially in the kidney. The VDR is present in multitudinous tissues, including many cancer cells, some with the capability to 1α-hydroxylate 25(OH)D3 to create the active 1,25(OH)2D3 and hence enabling locally initiated cellular proliferation and differentiation processes. While today's picture of the genomic responses, mediated by 1,25(OH)2D3, is somewhat coherent, the imputed non-genomic 'rapid responses' are more enigmatic. The medicinal chemist who seeks to intervene therapeutically in vitamin-D controlled gene transcription activity has reduced this intricate scenario to a working hypothesis based on a few facts and lemmas: Similar to other hormonal nuclear receptors, the VDR can modify gene expression by hormone-initiated signal transduction; 1,25(OH)2D3 induces co-localization of the VDR and RXR, the receptor activation unit, to the VDRE gene promoter rendering 1,25(OH)2D3 an essential component for gene expression. Cloning of the VDR and the availability of the VDR LBD crystal structure has not only illuminated the role of the receptor and its ligand in transcription regulation but also, to some extent, the physico-chemical requirements of the ligand. Add to this the dynamic behavior of the LBD with the resulting variations of transcriptional activity, the known endocrinal steering mechanism for the required cellular hormone levels through complex CYP-mediated metabolic pathway, and the chemical, biological and even clinical properties of vitamin D analogs previously prepared, and one arrives at an intriguing and exciting prospect to view vitamin D and its analogs as multifaceted tools implicated in a myriad of established and conjectured biological activities with a set of predefined preferences of molecular features. And therein are anchored the opportunities and challenges for the medicinal chemist. 1,25(OH)2D3 can suppress several growth factor and cytokine genes thus inhibiting the release of IL2, GM-CSF, interferon-γ, and PTH, for example. It regulates mineral homeostasis, cellular proliferation and differentiation, and autoimmune activities. The disease targets, envisioned for vitamin D analogs, appropriately, include osteoporosis by balancing bone-mineral mobilization, secondary hyperparathyroidism to reduce PTHgene transcription and blocking chief cell hyperplasia, autoimmune diseases such as psoriasis and asthma, organ-transplant rejection, benign prostate hyperplasia, involuntary bladder control, blood pressure control by suppressing renin biosynthesis, type 1 diabetes and insulin secretion by affecting pancreatic β-cell function, anti-inflammatory events via cyclooxygenase-2 inhibition, and cancer via the established antiproliferative and prodifferentiating effects on a variety of cell lines, such as breast, prostate and colon. The chemist must strive for selective molecular modifications of vitamin D to balance the potential function as a nuclear receptor agonist, antagonist or reverse agonist, and at the same time maintain tissue specificity and sufficient metabolic stability with a constant look out for hypercalcemia and hyperphosphatemia. While the discovery of agonist or even "superagonist" activity is the more popular goal in molecular design, the prospect of finding ligands that selectively stabilize an antagonistic conformation of the VDR LBD within the VDR-RXR-DVRE construct, to actually prevent induction of transactivation, is also of potential therapeutic value. The adaptability of the VDR to accept ligands that are deprived of many structural elements common to 1,25(OH)2D3 and demand drastically changed space requirements, however, underlines the difficulty to employ modern drug design technologies........