Vitamin D analogs--drug design based on proteins involved in vitamin D signal transduction

Vitamin D analogs have proven to be very valuable tools for the treatment of calcium-related diseases and certain hyperproliferative conditions such as renal osteodystrophy, psoriasis and cancer. In general, vitamin D analogs exploit the enzymic and receptor machinery of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signal transduction pathway. Key proteins in this cascade include the vitamin D receptor (VDR), the vitamin D-binding protein (DBP) and three cytochrome P450s (CYP27A, CYP27B and CYP24) which effect the synthesis and breakdown of the natural hormone, 1alpha,25(OH)(2)D(3). Analogs have been designed which reduce or enhance the importance of each of these proteins in the signal transduction pathway. Vitamin D prodrugs require one or more steps of activation and overcome congenital or acquired blocks in the 1alpha-hydroxylation step. By far the biggest class of vitamin D analogs are the VDR agonists which directly mimic 1alpha,25(OH)(2)D(3) and trigger protein conformational changes in the receptor which lead to changes in the transcriptional machinery at vitamin D-responsive genes. Other emerging classes of molecules include the VDR antagonists and CYP24 inhibitors which target different events in the cascade. This review assesses the relative importance of each of the proteins of the vitamin D cascade, evaluates the success of these modifications in tailoring drugs in all classes for selected disease states and contemplates future directions for the field.